Gpr40 agonists in anti-diabetic drug combinations

ABSTRACT

Disclosed are compositions comprising (a) a GPR40 agonist and (b) an SGLT2 inhibitor, and methods for treating of disorders that are affected by the modulation of the GPR40 receptor and SGLT2 transporter. Such GPR40 compounds are represented by Formula (I) as follows: 
     
       
         
         
             
             
         
       
     
     wherein ring W, R 1 , R 2 , R 3 , R 5 , R 6 , A, and Z, are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/320,822, filed Apr. 11, 2016, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a drug combination comprising (a) aGPR40 agonist of Formula (I) and (b) an SGLT2 inhibitor, for thetreatment of a disorder affected by the agonism of GPR40 and/orinhibition of SGLT2 transporter, and pharmaceutical compositionsthereof. The present invention further relates to the use of such drugcombinations and/or pharmaceutical compositions for the treatment ofvarious diseases, syndromes and disorders, including Type II diabetesmellitus, hyperglycemia, hyperinsulinemia, obesity, obesity-relateddisorders, impaired glucose tolerance, insulin resistance,hypertriglyceridemia, metabolic syndrome, diabetic complications,atherosclerosis, diabetic nephropathy, other cardiovascular risk factorssuch as hypertension and cardiovascular risk factors related tounmanaged cholesterol and/or lipid levels, osteoporosis, inflammation,and eczema, that are related to GPR40 and SGLT2 transporter modulation.

BACKGROUND OF THE INVENTION

According to WHO 2013 estimates, diabetes continues to present anincreasing health risk to the global population, affecting 347 millionindividuals worldwide. There are two main types of diabetes. Type 1diabetes, which affects ˜10% of diabetic patients, is characterized by adepletion of pancreatic insulin supply, resulting from an autoimmunedestruction of the insulin-producing beta-cells. Treatment requires theadministration of exogenous insulin in order to meet energy demands.Type 2 diabetes, which affects the vast majority (˜90%) of the diabeticpopulation, occurs when the body cannot effectively utilize the insulinthat is being produced. A number of factors may contribute to animpaired insulin response, including decreases in insulin production,insulin secretion or insulin sensitivity. In the initial stages of Type2 diabetes, most patients' beta cells undergo a compensatory expansionof functional mass and insulin output. As the disease progresses, thiscompensatory response eventually fails and pharmaceutical interventionis required in order to adequately regulate glucose levels. However,with further disease progression, the effectiveness of initiallyprescribed therapeutics generally declines, thus requiring additionalagents to be incorporated into the treatment regimen, each of whichcarries its own side-effect liability or risk.

Agents that reduce hepatic glucose production, the so-called biguanides,such as metformin or phenformin, are generally preferred as thefirst-line of treatment for newly-diagnosed patients. Glitazones, suchas rosiglitazone and pioglitazone function as insulin sensitizers (i.e.,enhance insulin action) through the activation of peroxisomeproliferator-activated receptor-γ (PPAR-γ). These agents can provide thebenefit of enhanced insulin action in tissues such as muscle, liver andadipose, but their use is frequently accompanied by increased weight andedema. In addition, rosiglitazone has recently been linked to heartattacks and its use has subsequently been more restricted. The insulinsecretagogue sulfonylureas (such as tolbutamide, chlorpropamide,glipizide or glyburide) enhance insulin secretion from functional betacells and are often combined with biguanide or glitazone therapy.However, because their effects on stimulating insulin release areindependent of glucose levels, the sulfonylureas bear the risk ofinducing incidences of hypoglycemia. Weight gain is also a commonside-effect from this compound class.

More recently, agents capable of inducing insulin secretion from betacells in a glucose-dependent fashion have been developed, based upon themechanisms of incretin peptide hormones (ex., GLP-1, GIP). Importantly,because of their glucose-dependent mechanisms of action, these agentsare able to provide glucose control while avoiding the risk ofhypoglycemia. The direct GLP-1 receptor agonists, Exendin-4 (Byetta®)and Liraglutide (Victoza®), which were engineered to provide enhancedmetabolic stabilities in vivo, have been developed as marketedbiological therapeutics. Dipeptidyl-peptidase-4 (DPP-4) inhibitors (theso-called, “gliptins” such as sitagliptin, saxagliptin, linagliptin,vildagliptin, anagliptin or alogliptin) inhibit the metabolicdegradation of endogenous incretins and thereby provide indirectincreases in insulin secretion in response to elevations in circulatingglucose levels.

Most recently, the recognition of GPR40 as a receptor whose activationenhances glucose-dependent insulin secretion has led to the search forselective agonists for this putative therapeutic target. GPR40, alsoknown as free fatty acid receptor 1 (FFR1), is one of a family ofG-protein coupled receptors that, through receptor deorphanizationstudies, was shown to be endogenously activated by medium- to long-chainsaturated and unsaturated fatty acids (˜C₁₂₋₂₀) (Brisco, et al., 2003, JBiol Chem, 278: 11303-11311; Itoh, et al., 2003, Nature, 422: 173-176;Kotarsky et al., 2003, Biochem Biophys Res Commun, 301: 406-410). Inhumans and rodents, although present in brain and enteroendocrine cells,its expression is particularly high in pancreatic beta cells. Operatingprimarily through Gα_(q/11) signaling, GPR40 activation of the beta cellleads to an increase in intracellular calcium levels, which in thepresence of glucose, ultimately results in augmented insulin secretion.In enteroendocrine cells, GPR40 activation by fatty acids leads tostimulation of incretin secretion (Edfalk, et al., 2008, Diabetes, 57:2280-2287). Thus, in addition to directly promoting GSIS from islet betacells, GPR40 activation in enteroendocrine cells provides an indirectmeans of stimulating GSIS through the actions of released incretins.

Because of the hyperglycemic dependency of GPR40-mediated effects oninsulin secretion, selective activation of this receptor provides aunique potential therapeutic mechanism by which to treat the diabeticstate with minimal risk of hypoglycemic incidents. Given the relativelyrestricted tissue expression pattern of GPR40, selective GPR40 agonistsmay offer the additional advantage of providing an improved safetyprofile relative to the aforementioned therapeutic agents.

SGLT2 is a 672 amino acid protein containing 14 membrane-spanningsegments that is predominantly expressed in the early S1 segment of therenal proximal tubules. Under physiological conditions, plasma glucoseis normally filtered in the kidney in the glomerulus and activelyreabsorbed in the proximal tubule. Ninety percent of glucose reuptake inthe kidney occurs in the epithelial cells of the early S1 segment of therenal cortical proximal tubule, and SGLT2 is likely to be the majortransporter responsible for this reuptake. The substrate specificity,sodium dependence, and localization of SGLT2 are consistent with theproperties of the high capacity, low affinity, sodium-dependent glucosetransporter previously characterized in human cortical kidney proximaltubules. In addition, hybrid depletion studies implicate SGLT2 as thepredominant Na⁺/glucose co-transporter in the S1 segment of the proximaltubule, since virtually all Na⁺-dependent glucose transport activityencoded in mRNA from rat kidney cortex is inhibited by an antisenseoligonucleotide specific to rat SGLT2 (Wright, et al., 2011, PhysiolRev. 91: 733-94). Selective inhibition of SGLT2 in diabetic patientswould be expected to normalize plasma glucose by enhancing the excretionof glucose in the urine, thereby improving insulin sensitivity, anddelaying the development of diabetic complications (Abdul-Ghani, et al.,2015, Amer J Physiol Renal Physiol. 309: F889-900; Ferrannini, et al.,2012, Nat Rev Endocrinol. 8:495-502).

SUMMARY OF THE INVENTION

The present invention is directed to a pharmaceutical compositioncomprising (a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein theGPR40 agonist is a compound of Formula (I)

wherein

-   -   ring W is phenyl or pyridyl;    -   A is —CH₂O— or —OCH₂—;    -   Z is CH or N;    -   R₆ is hydrogen;    -   R₁ is selected from hydrogen or methylacetylenyl; or R₁ and R₆        are taken together to form a spirofused 3-hydroxycyclobutyl or a        spirofused 3-oxocyclobutyl;    -   R₂ is selected from hydrogen or methyl;    -   R₃ is hydrogen, chloro, or a substituent selected from the group        consisting of C₁₋₃alkyl, hydroxy, 1,1-dioxothian-4-yl,        1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl,        1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, C₁₋₃alkylsulfonyl,        C₁₋₃alkylsulfonylamino,        1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl, piperidin-4-yl,        piperidin-4-ylmethyl, and —OR₄;    -   wherein R₄ is    -   i) C₁₋₈alkyl optionally independently substituted with one or        two C₁₋₃alkoxy or hydroxy substituents;    -   ii) C₃₋₇cycloalkyl;    -   iii) 4-hydroxy-1,1-dioxo-thian-4-ylmethyl;    -   iv) 1,1-dioxothian-4-yl;    -   v) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   vi) tetrahydro-2H-pyran-4-yl;    -   vii) C₁₋₃alkylsulfonylpropyl;    -   viii) 2-(1-hydroxycyclopropyl)ethyl;    -   ix) 3-methyloxetan-3-yl-methyl;    -   x) (3-methyl-1,1-dioxidothietan-3-yl)methyl;    -   xi) (1-C₃₋₆cycloalkyl-1-ol)methyl;    -   xii) 4-hydroxy-tetrahydropyran-4-ylmethyl;    -   xiii) 2-(C₃₋₇cycloalkyl)-2-hydroxyethyl;    -   xiv) tetrahydro-2H-pyran-4-ylmethyl;        -   or    -   xv) tetrahydrofuran-3-yl;    -   R₅ is methyl, methoxy, bromo, chloro, C₁₋₆alkoxy-C₁₋₆alkoxyl,        C₁₋₆alkylsulfonyl, or trifluoromethyl;        or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

The present invention also provides a pharmaceutical compositioncomprising, consisting of and/or consisting essentially of apharmaceutically acceptable carrier, a pharmaceutically acceptableexcipient, and/or a pharmaceutically acceptable diluent and a drugcombination comprising (a) a GPR40 agonist of Formula (I), or apharmaceutically acceptable salt form thereof, and (b) an SGLT2inhibitor.

Also provided are processes for making a pharmaceutical compositioncomprising, consisting of, and/or consisting essentially of admixing acomposition comprising (a) a GPR40 agonist of Formula (I) and (b) anSGLT2 inhibitor; and a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient, and/or a pharmaceuticallyacceptable diluent.

The present invention further provides methods for treating orameliorating a disease, syndrome, or condition in a subject, including amammal and/or human in which the disease, syndrome, or condition isaffected by the modulation of GPR40 and/or SGLT2 transporter, such asType II diabetes mellitus, using a composition comprising (a) a GPR40agonist of Formula (I), or a pharmaceutically acceptable salt formthereof, and (b) an SGLT2 inhibitor.

The present invention also is also directed to the use of thecomposition comprising (a) a GPR40 agonist of Formula (I), or apharmaceutically acceptable salt form thereof, and (b) an SGLT2inhibitor, in the preparation of a medicament wherein the medicament isprepared for treating a disease or condition selected from the groupconsisting of Type II diabetes mellitus, hyperglycemia,hyperinsulinemia, obesity, obesity-related disorders, impaired glucosetolerance, insulin resistance, hypertriglyceridemia, metabolic syndrome,diabetic complications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema, that are related to GPR40 andSGLT2 transporter modulation, in a subject in need thereof.

Exemplifying the invention are methods of treating a disorder modulatedby GPR40 and/or SGLT2 selected from the group consisting of Type IIdiabetes mellitus, hyperglycemia, hyperinsulinemia, obesity,obesity-related disorders, impaired glucose tolerance, insulinresistance, hypertriglyceridemia, metabolic syndrome, diabeticcomplications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema, that are related to GPR40 andSGLT2 modulation, comprising administering to a subject in need thereofa therapeutically effective amount of a composition comprising (a) aGPR40 agonist of Formula (I), or a pharmaceutically acceptable salt formthereof, and (b) an SGLT2 inhibitor; or pharmaceutical compositionthereof, as described above.

In another embodiment, the present invention is directed to acomposition comprising (a) a GPR40 agonist of Formula (I), or apharmaceutically acceptable salt form thereof, and (b) an SGLT2inhibitor for use in the treatment of a disorder affected by the agonismof GPR40 and/or inhibition of SGLT2 transporter, selected from the groupconsisting of Type II diabetes mellitus, hyperglycemia,hyperinsulinemia, obesity, obesity-related disorders, impaired glucosetolerance, insulin resistance, hypertriglyceridemia, metabolic syndrome,diabetic complications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema, that are related to GPR40 andSGLT2 transporter modulation.

In another embodiment, the present invention is directed to acomposition comprising (a) a GPR40 agonist of Formula (I), or apharmaceutically acceptable salt form thereof, and (b) an SGLT2inhibitor; for the treatment of a disorder affected by the agonism ofGPR40 and/or inhibition of SGLT2 transporter, selected from the groupconsisting of Type II diabetes mellitus, hyperglycemia,hyperinsulinemia, obesity, obesity-related disorders, impaired glucosetolerance, insulin resistance, hypertriglyceridemia, metabolic syndrome,diabetic complications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema, that are related to GPR40 andSGLT2 transporter modulation.

DETAILED DESCRIPTION OF THE INVENTION

With reference to substituents, the term “independently” refers to thesituation where when more than one substituent is possible, thesubstituents may be the same or different from each other.

The term “alkyl” whether used alone or as part of a substituent group,refers to straight and branched carbon chains having 1 to 8 carbonatoms. Therefore, designated numbers of carbon atoms (e.g., C₁₋₈) referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. In substituentgroups with multiple alkyl groups such as, (C₁₋₆alkyl)₂amino-, theC₁₋₆alkyl groups of the dialkylamino may be the same or different.

The term “alkoxy” refers to an —O-alkyl group, wherein the term “alkyl”is as defined above.

The terms “alkenyl” and “alkynyl” refer to straight and branched carbonchains having 2 to 8 carbon atoms, wherein an alkenyl chain contains atleast one double bond and an alkynyl chain contains at least one triplebond.

The term “cycloalkyl” refers to saturated or partially saturated,monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atoms.Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and adamantyl.

The term “heterocyclyl” refers to a nonaromatic monocyclic or bicyclicring system having 3 to 10 ring members that include at least 1 carbonatom and from 1 to 4 heteroatoms independently selected from N, O, andS. Included within the term heterocyclyl is a nonaromatic cyclic ring of5 to 7 members in which 1 to 2 members are N, or a nonaromatic cyclicring of 5 to 7 members in which 0, 1 or 2 members are N and up to 2members are 0 or S and at least one member must be either N, O, or S;wherein, optionally, the ring contains 0 to 1 unsaturated bonds, and,optionally, when the ring is of 6 or 7 members, it contains up to 2unsaturated bonds. The carbon atom ring members that form a heterocyclering may be fully saturated or partially saturated. The term“heterocyclyl” also includes two 5 membered monocyclic heterocycloalkylgroups bridged to form a bicyclic ring. Such groups are not consideredto be fully aromatic and are not referred to as heteroaryl groups. Whena heterocycle is bicyclic, both rings of the heterocycle arenon-aromatic and at least one of the rings contains a heteroatom ringmember. Examples of heterocycle groups include, and are not limited to,pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unlessotherwise noted, the heterocycle is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

The term “aryl” refers to an unsaturated, aromatic monocyclic orbicyclic ring of 6 to 10 carbon members. Examples of aryl rings includephenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic monocyclic or bicyclicaromatic ring system having 5 to 10 ring members and which containscarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O, and S. Included within the term heteroaryl arearomatic rings of 5 or 6 members wherein the ring consists of carbonatoms and has at least one heteroatom member. Suitable heteroatomsinclude nitrogen, oxygen, and sulfur. In the case of 5 membered rings,the heteroaryl ring preferably contains one member of nitrogen, oxygenor sulfur and, in addition, up to 3 additional nitrogens. In the case of6 membered rings, the heteroaryl ring preferably contains from 1 to 3nitrogen atoms. For the case wherein the 6 membered ring has 3nitrogens, at most 2 nitrogen atoms are adjacent. Examples of heteroarylgroups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unlessotherwise noted, the heteroaryl is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine atoms.

The term “carboxy” refers to the group —C(═O)OH.

The term “formyl” refers to the group —C(═O)H.

The term “oxo” or “oxido” refers to the group (═O).

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a sub stituent (e.g., arylalkyl, alkylamino) thename is to be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)refer independently to the number of carbon atoms in an alkyl moiety, anaryl moiety, or in the alkyl portion of a larger substituent in whichalkyl appears as its prefix root. For alkyl and alkoxy substituents, thedesignated number of carbon atoms includes all of the independentmembers included within a given range specified. For example C₁₋₆ alkylwould include methyl, ethyl, propyl, butyl, pentyl and hexylindividually as well as sub-combinations thereof (e.g., C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅ C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “C₁-C₆ alkylcarbonyl” sub stituentrefers to a group of the formula:

The term “R” at a stereocenter designates that the stereocenter ispurely of the R-configuration as defined in the art; likewise, the term“S” means that the stereocenter is purely of the S-configuration. Asused herein, the terms “*R” or “*S” at a stereocenter are used todesignate that the stereocenter is of pure but unknown configuration. Asused herein, the term “RS” refers to a stereocenter that exists as amixture of the R- and S-configurations. Similarly, the terms “*RS” or“*SR” refer to a stereocenter that exists as a mixture of the R- andS-configurations and is of unknown configuration relative to anotherstereocenter within the molecule.

Compounds containing one stereocenter drawn without a stereo bonddesignation are a mixture of two enantiomers. Compounds containing twostereocenters both drawn without stereo bond designations are a mixtureof four diastereomers. Compounds with two stereocenters both labeled“RS” and drawn with stereo bond designations are a two-component mixturewith relative stereochemistry as drawn. Compounds with two stereocentersboth labeled “*RS” and drawn with stereo bond designations are atwo-component mixture with relative stereochemistry unknown. Unlabeledstereocenters drawn without stereo bond designations are a mixture ofthe R- and S-configurations. For unlabeled stereocenters drawn withstereo bond designations, the absolute stereochemistry is as depicted.

Unless otherwise noted, it is intended that the definition of anysubstituent or variable at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. It isunderstood that substituents and substitution patterns on the compoundsof the present invention can be selected by one of ordinary skill in theart to provide compounds that are chemically stable and that can bereadily synthesized by techniques known in the art as well as thosemethods set forth herein.

The term “subject” refers to an animal, preferably a mammal, mostpreferably a human, who has been the object of treatment, observation orexperiment.

The term “therapeutically effective amount” refers to an amount of anactive compound or pharmaceutical agent, including a compound of thepresent invention, which elicits the biological or medicinal response ina tissue system, animal or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includesalleviation or partial alleviation of the symptoms of the disease,syndrome, condition, or disorder being treated.

The term “composition” refers to a product that includes the specifiedingredients in therapeutically effective amounts, as well as any productthat results, directly, or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “GPR40 agonist” is intended to encompass a compound thatinteracts with GPR40 to substantially increase its downstream signaling,thereby resulting in physiologic effects such as, but not limited to,insulin secretion in the pancreas.

The term “GPR40 receptor-modulated” is used to refer to the condition ofbeing affected by the modulation of the GPR40 receptor, including butnot limited to, the state of being mediated by the GPR40 receptor, forthe treatment of a disease or condition such as Type II diabetes orimpaired glucose tolerance.

As used herein, unless otherwise noted, the term “disorder modulated bythe GPR40 receptor” shall mean any disease, disorder or conditioncharacterized in that at least one of its characteristic symptoms isalleviated or eliminated upon treatment with a GPR40 receptor agonist.Suitably examples include, but are not limited to Type II diabetesmellitus, obesity, obesity-related disorders, impaired glucosetolerance, insulin resistance, metabolic syndrome, other cardiovascularrisk factors such as hypertension and cardiovascular risk factorsrelated to unmanaged cholesterol and/or lipid levels, osteoporosis,inflammation, and eczema; more preferably, Type II diabetes mellitus andimpaired glucose tolerance.

As used herein unless otherwise noted, the term “cardiovascular riskfactors” shall mean any cardiovascular disease, disorder or condition inwhich obesity or diabetes (preferably, Type II diabetes) has a role inthe initiation or exacerbation of said disorder or condition. Suitableexamples include, but are not limited to, hypertension, atherosclerosisand cardiac fibrosis.

The term “SGLT2 inhibitor” is intended to encompass a compound thatinteracts with SGLT2 and promotes urinary excretion of glucose bypreventing its tubular reabsorption.

The term “SGLT2 inhibitor-modulated” is used to refer to the conditionof being affected by the modulation of the SGLT2 transporter, includingbut not limited to, the state of being mediated by the SGLT2transporter, for the treatment of a disease or condition such as Type IIdiabetes or impaired glucose tolerance.

As used herein, unless otherwise noted, the term “affect” or “affected”(when referring to a disease, syndrome, condition or disorder that isaffected by agonism of GPR40 or by inhibition of SGLT2 transporter)includes a reduction in the frequency and/or severity of one or moresymptoms or manifestations of said disease, syndrome, condition ordisorder; and/or include the prevention of the development of one ormore symptoms or manifestations of said disease, syndrome, condition ordisorder or the development of the disease, condition, syndrome ordisorder.

The compounds of the instant invention are useful in methods fortreating or ameliorating a disease, a syndrome, a condition or adisorder that is affected by the agonism of GPR40 receptor and/orinhibition of SGLT2 transporter. Such methods comprise, consist ofand/or consist essentially of administering to a subject, including ananimal, a mammal, and a human in need of such treatment, ameliorationand/or prevention, a therapeutically effective amount of apharmaceutical composition composition comprising (a) a GPR40 agonist ofFormula (I), or a pharmaceutically acceptable salt form thereof, and (b)an SGLT2 inhibitor.

In particular, the pharmaceutical composition of the present invention,or a pharmaceutically acceptable salt form thereof, is useful fortreating or ameliorating diseases, syndromes, conditions, or disorderssuch as Type II diabetes mellitus, hyperglycemia, hyperinsulinemia,obesity, obesity-related disorders, impaired glucose tolerance, insulinresistance, hypertriglyceridemia, metabolic syndrome, diabeticcomplications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema, that are related to GPR40 andSGLT2 transporter modulation.

More particularly, the pharmaceutical composition of the presentinvention, or a pharmaceutically acceptable salt form thereof, is usefulfor treating or ameliorating Type II diabetes mellitus or impairedglucose tolerance, comprising administering to a subject in need thereofa therapeutically effective amount of a combination of (a) a GPR40agonist of Formula (I), or a pharmaceutically acceptable salt formthereof, and (b) an SGLT2 inhibitor.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein the GPR40agonist is a compound of Formula (I)

wherein

-   a) ring W is phenyl;-   b) ring W is pyridyl;-   c) A is —CH₂O—;-   d) A is —OCH₂—;-   e) Z is CH, R₆ is hydrogen and R₁ is (S)-methylacetylenyl; or R₁ and    R₆ are taken together to form a spirofused 3-hydroxycyclobutyl or a    spirofused 3-oxocyclobutyl;-   f) Z is N, R₆ is hydrogen and R₁ is (R)-methylacetylenyl; or R₁ and    R₆ are taken together to form a spirofused 3-hydroxycyclobutyl or a    spirofused 3-oxocyclobutyl;-   g) R₂ is hydrogen;-   h) R₃ is hydrogen, chloro, or a substituent selected from the group    consisting of C₁₋₃alkyl, hydroxy, 1,1-dioxothian-4-yl,    1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl,    1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, C₁₋₃alkylsulfonyl,    C₁₋₃alkylsulfonylamino,    1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl, piperidin-4-yl,    piperidin-4-ylmethyl, and —OR₄;    -   wherein R₄ is    -   i) C₁₋₈alkyl optionally independently substituted with one or        two C₁₋₃alkoxy or hydroxy substituents;    -   ii) C₃₋₇cycloalkyl;    -   iii) 4-hydroxy-1,1-dioxo-thian-4-ylmethyl;    -   iv) 1,1-dioxothian-4-yl;    -   v) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   vi) tetrahydro-2H-pyran-4-yl;    -   vii) C₁₋₃alkylsulfonylpropyl;    -   viii) 2-(1-hydroxycyclopropyl)ethyl;    -   ix) 3-methyloxetan-3-yl-methyl;    -   x) (3-methyl-1,1-dioxidothietan-3-yl)methyl;    -   xi) tetrahydro-2H-pyran-4-ylmethyl;        -   or    -   xii) tetrahydrofuran-3-yl;-   i) R₃ is hydrogen or a substituent that is —OR₄;    -   wherein R₄ is    -   i) C₁₋₄alkyl optionally independently substituted with one or        two hydroxy or C₁₋₃alkoxy substituents;    -   ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;    -   iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   iv) tetrahydro-2H-pyran-4-yl;    -   v) C₁₋₃alkylsulfonylpropyl;    -   vi) tetrahydro-2H-pyran-4-ylmethyl;        -   or    -   vii) tetrahydrofuran-3-yl;-   j) R₃ is selected from the group consisting of hydrogen; methyl;    hydroxy; chloro; (4-hydroxy-1,1-dioxo-thian-4-yl)methoxy;    4-(3-methylsulfonylpropoxy; 1,1-dioxo-1,4-thiazinane-4-carbonyl;    1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl; 1,1-dioxothian-4-yl;    (1,1-dioxothian-4-yl)oxy; (1-hydroxycyclopropyl)ethoxy;    3-hydroxy-3-methylbutoxy; 2,3-dihydroxypropoxy;    (3-methyloxetan-3-yl)methoxy; (tetrahydro-2H-pyran-4-yl)oxy;    2-methoxyethoxy; (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy;    (3-methyl-1,1-dioxidothietan-3-yl)methoxy;    (3-(methylsulfonyl)propoxy; 1,1-dioxidotetrahydro-2H-thiopyran-4-yl;    2-ethoxyethoxy; 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy;    (tetrahydro-2H-pyran-4-yl)oxy;    1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl; methyl sulfonyl;    methylsulfonamido; piperidin-4-yl; piperidin-4-ylmethyl; and    tetrahydro-2H-pyran-4-yl)oxy;-   k) R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,    or trifluoromethyl;

and any combination of embodiments a) through k) above, provided that itis understood that combinations in which different embodiments of thesame substituent would be combined are excluded; or an enantiomer,diastereomer, or pharmaceutically acceptable salt form thereof.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein the GPR40agonist is a compound of Formula (I)

wherein

-   -   ring W is phenyl or pyridyl;    -   A is —CH₂O— or —OCH₂—;    -   Z is CH or N;    -   R₆ is hydrogen;    -   R₁ is selected from hydrogen or methylacetylenyl; or R₁ and R₆        are taken together to form a spirofused 3-hydroxycyclobutyl or a        spirofused 3-oxocyclobutyl;

R₂ is hydrogen;

R₃ is hydrogen, chloro, or a substituent selected from the groupconsisting of C₁-3alkyl, hydroxy, 1,1-dioxothian-4-yl,1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl,1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, C₁₋₃alkyl sulfonyl,C₁₋₃alkylsulfonylamino, 1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl,piperidin-4-yl, piperidin-4-ylmethyl, and —OR₄;

-   -   wherein R₄ is    -   i) C₁₋₈alkyl optionally independently substituted with one or        two C₁₋₃alkoxy or hydroxy substituents;    -   ii) C₃₋₇cycloalkyl;    -   iii) 4-hydroxy-1,1-dioxo-thian-4-ylmethyl;    -   iv) 1,1-dioxothian-4-yl;    -   v) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   vi) tetrahydro-2H-pyran-4-yl;    -   vii) C₁₋₃alkylsulfonylpropyl;    -   viii) 2-(1-hydroxycyclopropyl)ethyl;    -   ix) 3-methyloxetan-3-yl-methyl;    -   x) (3-methyl-1,1-dioxidothietan-3-yl)methyl;    -   xi) tetrahydro-2H-pyran-4-ylmethyl;        -   or    -   xii) tetrahydrofuran-3-yl;    -   R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,        or trifluoromethyl;    -   or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein the GPR40agonist is a compound of Formula (I)

wherein

-   -   ring W is phenyl or pyridyl;    -   A is —CH₂O— or —OCH₂—;    -   when Z is CH, R₆ is hydrogen and R₁ is (S)-methylacetylenyl; or        R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;    -   or, when Z is N, R₆ is hydrogen and R₁ is (R)-methylacetylenyl;        or R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;    -   R₂ is hydrogen;    -   R₃ is hydrogen, chloro, or a substituent selected from the group        consisting of C₁₋₃alkyl, hydroxy, 1,1-dioxothian-4-yl,        1,1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl,        1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, C₁₋₃alkylsulfonyl,        C₁₋₃alkyl sulfonylamino,        1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl, piperidin-4-yl,        piperidin-4-ylmethyl, and —OR₄;    -   wherein R₄ is    -   i) C₁₋₈alkyl optionally independently substituted with one or        two C₁₋₃alkoxy or hydroxy substituents;    -   ii) C₃₋₇cycloalkyl;    -   iii) 4-hydroxy-1,1-dioxo-thian-4-ylmethyl;    -   iv) 1,1-dioxothian-4-yl;    -   v) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   vi) tetrahydro-2H-pyran-4-yl;    -   vii) C₁₋₃alkylsulfonylpropyl;    -   viii) 2-(1-hydroxycyclopropyl)ethyl;    -   ix) 3-methyloxetan-3-yl-methyl;    -   x) (3-methyl-1,1-dioxidothietan-3-yl)methyl;    -   xi) tetrahydro-2H-pyran-4-ylmethyl;        -   or    -   xii) tetrahydrofuran-3-yl;    -   R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,        or trifluoromethyl;    -   or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein the GPR40agonist is a compound of Formula (I)

wherein

-   -   ring W is pyridyl;    -   A is —CH₂O— or —OCH₂—;    -   Z is CH, R₆ is hydrogen and R₁ is (S)-methylacetylenyl; or R₁        and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl; or    -   Z is N, R₆ is hydrogen and R₁ is (R)-methylacetylenyl; or R₁ and        R₆ are taken together to form a spirofused 3-hydroxycyclobutyl        or a spirofused 3-oxocyclobutyl;    -   R₂ is hydrogen;    -   R₃ is hydrogen or a substituent that is —OR₄;        wherein R₄ is    -   i) C₁₋₄alkyl optionally independently substituted with one or        two hydroxy or C₁₋₃alkoxy substituents;    -   ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;    -   iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   iv) tetrahydro-2H-pyran-4-yl;    -   v) C₁₋₃alkylsulfonylpropyl;    -   vi) tetrahydro-2H-pyran-4-ylmethyl;        -   or    -   vii) tetrahydrofuran-3-yl;    -   R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,        or trifluoromethyl;    -   or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein the GPR40agonist is a compound of Formula (I)

wherein

-   -   ring W is phenyl;    -   A is —CH₂O— or —OCH₂—;    -   when Z is CH, R₆ is hydrogen and R₁ is (S)-methylacetylenyl; or        R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl; or    -   when Z is N, R₆ is hydrogen and R₁ is (R)-methylacetylenyl; or        R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;    -   R₂ is hydrogen;    -   R₃ is hydrogen or a substituent that is piperidin-4-yl,        piperidin-4-ylmethyl, or —OR₄;    -   wherein R₄ is    -   i) C₁₋₄alkyl optionally independently substituted with one or        two hydroxy or C₁₋₃alkoxy substituents;    -   ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;    -   iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   iv) tetrahydro-2H-pyran-4-yl;    -   v) C₁₋₃alkylsulfonylpropyl;    -   vi) tetrahydro-2H-pyran-4-ylmethyl; or    -   vii) tetrahydrofuran-3-yl;    -   R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,        or trifluoromethyl;    -   or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein the GPR40agonist is a compound of Formula (I)

wherein

-   -   ring W is phenyl or pyridyl;    -   A is —CH₂O—;    -   when Z is CH, R₆ is hydrogen and R₁ is (S)-methylacetylenyl; or        R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl; or    -   when Z is N, R₆ is hydrogen and R₁ is (R)-methylacetylenyl; or        R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;    -   R₂ is hydrogen;    -   R₃ is hydrogen or a substituent that is —OR₄;    -   wherein R₄ is    -   i) C₁₋₄alkyl optionally independently substituted with one or        two hydroxyl or C₁₋₃alkoxy substituents;    -   ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;    -   iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;    -   iv) tetrahydro-2H-pyran-4-yl;    -   v) C₁₋₃alkylsulfonylpropyl;    -   vi) tetrahydro-2H-pyran-4-ylmethyl; or    -   vii) tetrahydrofuran-3-yl;    -   R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,        or trifluoromethyl;        or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein thesa GPR40agonist is a compound of Formula (I)

wherein

-   -   ring W is phenyl or pyridyl;    -   A is —CH₂O— or —OCH₂—;    -   Z is CH or N    -   R₆ is hydrogen;    -   R₁ is selected from hydrogen or methylacetylenyl; or R₁ and R₆        are taken together to form a spirofused 3-hydroxycyclobutyl or a        spirofused 3-oxocyclobutyl;    -   R₂ is selected from hydrogen or methyl;    -   R₃ is selected from the group consisting of hydrogen; methyl;        methoxy; hydroxy; chloro;        (4-hydroxy-1,1-dioxo-thian-4-yl)methoxy;        4-(3-methylsulfonylpropoxy; 1,1-dioxo-1,4-thiazinane-4-carbonyl;        1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl;

-   1,1-dioxothian-4-yl; (1,1-dioxothian-4-yl)oxy;    (1-hydroxycyclopropyl)ethoxy; 3-hydroxy-3-methylbutoxy;    2,3-dihydroxypropoxy; (3-methyloxetan-3-yl)methoxy;    (tetrahydro-2H-pyran-4-yl)oxy; 2-methoxyethoxy;    (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy;    (3-methyl-1,1-dioxidothietan-3-yl)methoxy;    (3-(methylsulfonyl)propoxy; 1,1-dioxidotetrahydro-2H-thiopyran-4-yl;    2-ethoxyethoxy; 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy;    (tetrahydro-2H-pyran-4-yl)oxy;    1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl; methylsulfonyl;    methylsulfonamido; 3-hydroxy-3-methylbutoxy;    tetrahydro-2H-pyran-4-yl)methoxy; tetrahydrofuran-3-yloxy;    piperidin-4-yl; piperidin-4-ylmethyl; and    tetrahydro-2H-pyran-4-yl)oxy;    -   R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,        or trifluoromethyl;    -   or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

Embodiments of the present invention include a composition comprising(a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein the GPR40agonist is a compound of Formula (I)

wherein

-   -   ring W is phenyl or pyridyl;    -   A is —CH₂O— or —OCH₂—;    -   when Z is CH, R₆ is hydrogen and R₁ is (S)-methylacetylenyl; or        R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;    -   or    -   when Z is N, R₆ is hydrogen and R₁ is (R)-methylacetylenyl; or        R₁ and R₆ are taken together to form a spirofused        3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;    -   R₂ is selected from hydrogen or methyl;    -   R₃ is selected from the group consisting of hydrogen; methyl;        methoxy; hydroxy; chloro;        (4-hydroxy-1,1-dioxo-thian-4-yl)methoxy;        4-(3-methylsulfonylpropoxy; 1,1-dioxo-1,4-thiazinane-4-carbonyl;        1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl; 1,1-dioxothian-4-yl;        (1,1-dioxothian-4-yl)oxy; (1-hydroxycyclopropyl)ethoxy;        3-hydroxy-3-methylbutoxy; 2,3-dihydroxypropoxy;        (3-methyloxetan-3-yl)methoxy; (tetrahydro-2H-pyran-4-yl)oxy;        2-methoxyethoxy;        (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy;        (3-methyl-1,1-dioxidothietan-3-yl)methoxy;        (3-(methylsulfonyl)propoxy; 1,1-di        oxidotetrahydro-2H-thiopyran-4-yl; 2-ethoxyethoxy;        1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy;        (tetrahydro-2H-pyran-4-yl)oxy;        1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl; methylsulfonyl;        methylsulfonamido; 3-hydroxy-3-methylbutoxy;        tetrahydro-2H-pyran-4-yl)methoxy; tetrahydrofuran-3-yloxy;        piperidin-4-yl; piperidin-4-ylmethyl; and        tetrahydro-2H-pyran-4-yl)oxy;    -   R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro,        or trifluoromethyl;        or an enantiomer, diastereomer, or pharmaceutically acceptable        salt form thereof.

A further embodiment of the present invention is directed to acomposition comprising (a) a GPR40 agonist of Formula (I) and (b) anSGLT2 inhibitor; wherein the GPR40 agonist is3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 97

A further embodiment of the present invention is directed to acomposition comprising (a) a GPR40 agonist of Formula (I) and (b) anSGLT2 inhibitor; wherein the GPR40 agonist is(3S)-3-[4-[[3-(2-methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 2

Additional embodiments of the present invention include a compositioncomprising (a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein theGPR40 agonist is a compound of Formula (I), as herein defined, or anenantiomer, diastereomer, solvate, or a pharmaceutically acceptable saltform thereof, as exemplified in the listing in Table 1, below.

TABLE 1 Structure Cpd No. Cpd Name

 1 3-[4-[[3-(2- Methylphenyl)benzo[b]thiophen- 5-yl]methoxy]phenyl]propanoic acid

 2 (3S)-3-[4-[[3-(2- Methylphenyl)benzo[b]thiophen- 5-yl]methoxy]phenyl]hex-4-ynoic acid

 3 (3S)-3-[4-[[3-[4-[(4-Hydroxy- 1,1-dioxo-thian-4-yl)methoxy]-2-methyl-phenyl]benzo[b] thiophen-5-yl]methoxy]phenyl] hex-4-ynoic acid

 4 (3S)-3-[4-[[3-[2-Methyl-4-(3- methylsulfonylpropoxy)phenyl]benzo[b]thiophen-5- yl]methoxy]phenyl] hex-4-ynoic acid

 5 (3S)-3-[4-[[3-[4-(1,1-Dioxo-1,4- thiazinane-4-carbonyl)-2- methyl-phenyl]benzo[b]thiophen-5- yl]methoxy]phenyl] hex-4-ynoic acid

 6 (3S)-3-[4-[[3-[4-(1,1-Dioxo-3,6- dihydro-2H-thiopyran-4-yl)-2-methyl- phenyl]benzo[b]thiophen-5- yl]methoxy]phenyl] hex-4-ynoic acid

 7 (3S)-3-[4-[[3-(4-Hydroxy-2- methyl- phenyl)benzo[b]thiophen-5-yl]methoxy]phenyl] hex-4-ynoic acid

 8 (3S)-3-[4-[[3-[4-(1,1- Dioxothian-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5- yl]methoxy]phenyl] hex-4-ynoic acid

 9 (3S)-3-[4-[[3-[4-(1,1- Dioxothian-4-yl)oxy-2-methyl-phenyl]-2-methyl- benzo[b]thiophen-5- yl]methoxy]phenyl] hex-4-ynoicacid

10 (3S)-3-[4-[[3-(2,6- Dimethylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl] hex-4-ynoic acid

11 (3S)-3-(4-((3-(4-(2-(1- Hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl) hex-4-ynoic acid

12 (3S)-3-(4-((3-(4-(3-Hydroxy-3- methylbutoxy)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl) hex-4-ynoic acid

13 (3S)-3-(4-((3-(4-(2,3- Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl) hex-4-ynoic acid

14 (3S)-3-(4-((3-(2-Methyl-4-((3- methyloxetan-3-yl)methoxy)phenyl)benzo[b] thiophen-5-yl)methoxy)phenyl) hex-4-ynoicacid

15 (3S)-3-(4-((3-(2-Methyl-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl) hex-4-ynoic acid

16 (3S)-3-(4-((3-(4-(2- Methoxyethoxy)-2- methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

17 (3S)-3-(4-((3-(4-((1,1- Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2- methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

18 (3S)-3-(4-((3-(2-Methyl-4-((3- methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b] thiophen-5-yl)methoxy)phenyl) hex-4-ynoicacid

19 (3S)-3-(4-((3-(2- Chlorophenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)hex-4-ynoic acid

20 (3S)-3-(4-((3-(2- Bromophenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)hex-4-ynoic acid

21 (3S)-3-(4-((3-(2- (Trifluoromethyl)phenyl)benzo [b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

22 (3S)-3-(4-((3-(2-Methylpyridin- 3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

23 (3S)-3-(4-(((3-(2- Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl) hex-4-ynoic acid

24 (3S)-3-(4-(((3-(2-Methyl-4-(3- (methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5- yl)oxy)methyl)phenyl) hex-4-ynoic acid

25 (3S)-3-(4-(((3-(4-(1,1-Dioxido- 3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl) benzo[b]thiophen-5- yl)oxy)methyl)phenyl) hex-4-ynoicacid

26 (3S)-3-(4-(((3-(4-(1,1- Dioxidotetrahydro-2H- thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen- 5-yl)oxy)methyl)phenyl) hex-4-ynoic acid

27 (3S)-3-(4-(((3-(2,6- Dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl) hex-4-ynoic acid

28 2-(1-(4-((3-(4-(1,1-Dioxido-3,6- dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid

29 2-(1-(4-((3-(4-(1,1- Dioxidotetrahydro-2H- thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid

30 2-(3-Oxo-1-(4-((3-(2- methylphenyl) benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl) acetic acid

31 2-((1r,3r)-3-Hydroxy-1-(4-((3- (2-methylphenyl) benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl) acetic acid

32 2-(1-(4-((3-(4-(2- Ethoxyethoxy)-2- methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3- oxocyclobutyl)acetic acid

33 2-(1-(4-((3-(4-((1,1- Dioxidotetrahydro-2H- thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid

34 2-(1-(4-((3-(2-Methyl-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid

35 2-((1r,3r)-3-Hydroxy-1-(4-((3- (4-(2-ethoxyethoxy)-2- methylphenyl)benzo[b]thiophen-5- yl)methoxy)phenyl)cyclobutyl) acetic acid

36 2-((1r,3r)-1-(4-((3-(4-((1,1- Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2- methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3- hydroxycyclobutyl)acetic acid

37 2-((1r,3r)-3-Hydroxy-1-(4-((3- (2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl) benzo[b]thiophen-5- yl)methoxy)phenyl)cyclobutyl)acetic acid

38 2-(1-(4-((3-(2-Methylpyridin-3- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3- oxocyclobutyl)acetic acid

39 2-((1r,3r)-3-Hydroxy-1-(4-((3- (2-methylpyridin-3-yl)benzo[b]thiophen-5- yl)methoxy)phenyl)cyclobutyl) acetic acid

40 2-(1-(4-((3-(4-(1,1-Dioxido-1- thia-6-azaspiro[3.3] heptan-6-yl)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid

41 (3S)-3-(4-((3-(2-Methyl-5- (methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

42 (3S)-3-(4-((3-(2-Methyl-4- (methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

43 (3S)-3-(4-((3-(2-Methyl-5- (methylsulfonamido)phenyl)benzo[b]thiophen-5- yl)methoxy)phenyl) hex-4-ynoic acid

44 (3S)-3-(4-((3-(2-Methyl-6- (methylsulfonamido)phenyl)benzo[b]thiophen-5- yl)methoxy)phenyl) hex-4-ynoic acid

45 3-(6-((3-(2- Methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

46 3-(6-((3-(2-Methyl-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen- 5-yl)methoxy)pyridin-3-yl) hex-4-ynoicacid

47 3-(6-((3-(4-(2-Methoxyethoxy)- 2-methylphenyl) benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

48 (3S)-3-(4-((3-(5-(2- Methoxyethoxy)-3- methylpyridin-2-yl)benzo[b]thiophen-5- yl)methoxy)phenyl) hex-4-ynoic acid

49 (3S)-3-(4-((3-(5-(2- Methoxyethoxy)-2- methylpyridin-3-yl)benzo[b]thiophen-5- yl)methoxy)phenyl) hex-4-ynoic acid

50 (3S)-3-(4-((3-(6-(2- Methoxyethoxy)-2- methylpyridin-3-yl)benzo[b]thiophen-5- yl)methoxy)phenyl) hex-4-ynoic acid

51 (3S)-3-(4-((3-(6-(2- Methoxyethoxy)-4- methylpyridin-3-yl)benzo[b]thiophen-5- yl)methoxy)phenyl) hex-4-ynoic acid

52 (3S)-3-(4-((3-(2-Chloro-5- methylpyridin-4- yl)benzo[b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

53 3-(4-(((3-(2- Methylphenyl)benzo[b]thiophen- 5-yl)oxy)methyl)phenyl)propanoic acid

54 (3S)-3-[4-[([3-[4-(3-Hydroxy-3- methylbutoxy)-2- methylphenyl]-1-benzothiophen-5- yl]oxy)methyl]phenyl] hex-4-ynoic acid

55 (3S)-3-[4-[([3-[4-(2,3- Dihydroxypropoxy)-2- methylphenyl]-1-benzothiophen-5- yl]oxy)methyl]phenyl] hex-4-ynoic acid

56 (3S)-3-(4-[[(3-[2-Methyl-4-[(3- methyloxetan-3- yl)methoxy]phenyl]-1-benzothiophen-5- yl)oxy]methyl]phenyl) hex-4-ynoic acid

57 (3S)-3-[4-[([3-[2-Methyl-4- (oxan-4-yloxy)phenyl]-1- benzothiophen-5-yl]oxy)methyl]phenyl] hex-4-ynoic acid

58 (3S)-3-[4-[([3-[4-(2- Methoxyethoxy)-2- methylphenyl]-1-benzothiophen-5- yl]oxy)methyl]phenyl] hex-4-ynoic acid

59 (3S)-3-{4-[((3-{4-[(1,1-Dioxo- tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}- 1-benzothiophen-5- yl)oxy)methyl]phenyl}hex-4-ynoic acid

60 (3S)-3-(4-(((3-(2-Methyl-4-((3- methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b] thiophen-5-yl)oxy)methyl)phenyl) hex-4-ynoicacid

61 3-[6-([3-[4-(3-Hydroxy-3- methylbutoxy)-2- methylphenyl]-1-benzothiophen-5- yl]methoxy)pyridin-3-yl] hex-4-ynoic acid

62 3-(6-((3-(4-(2,3- Dihydroxypropoxy)-2- methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

63 3-(6-((3-(4-((1,1- Dioxidotetrahydro-2H- thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)pyridin-3-yl) hex-4-ynoicacid

64 3-(6-((3-(2-Methyl-4-((3- methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b] thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid

65 (3S)-3-[4-([3-[5-(2- Methoxyethoxy)-2- methylphenyl]-1-benzothiophen-5- yl]methoxy)phenyl] hex-4-ynoic acid

66 (3S)-3-[4-([3-[2-(2- Methoxyethoxy)-6- methylphenyl]-1-benzothiophen-5- yl]methoxy)phenyl] hex-4-ynoic acid

67 (3S)-3-[4-([3-[3-(2- Methoxyethoxy)-2- methylphenyl]-1-benzothiophen-5- yl]methoxy)phenyl] hex-4-ynoic acid

68 (3S)-3-[4-([3-[2-(2- Methoxyethoxy)phenyl]-1- benzothiophen-5-yl]methoxy)phenyl] hex-4-ynoic acid

69 (3S)-3-(4-[[3-(2- Methanesulfonylphenyl)-1- benzothiophen-6-yl]methoxy]phenyl) hex-4-ynoic acid

70 (3S)-3-(6-((3-(4-(3-Hydroxy-3- methylbutoxy)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)pyridin-3-yl)hex- 4-ynoicacid

71 (3R)-3-(6-((3-(4-(3-Hydroxy-3- methylbutoxy)-2-methylphenyl)benzo[b]thiophen- 5-yl)methoxy)pyridin-3-yl)hex- 4-ynoicacid

72 (3S)-3-(6-((3-(2-Methyl-4- ((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b] thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid

73 (3R)-3-(6-((3-(2-Methyl-4- ((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b] thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid

74 (3S)-3-(6-((3-(4-((1,1- Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2- methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

75 (3R)-3-(6-((3-(4-((1,1- Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2- methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

76 (3S)-3-(6-((3-(4-(2- Methoxyethoxy)-2- methylphenyl)benzo[b]thiophen-5- yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

77 (3R)-3-(6-((3-(4-(2- Methoxyethoxy)-2- methylphenyl)benzo[b]thiophen-5- yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

78 (3S)-3-(4-((3-(2- Methoxypyridin-3- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

79 (3S)-3-(4-((3-(2- Methoxyphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4- ynoic acid

80 (3S)-3-(4-((3-(6-Methoxy-2- methylpyridin-3- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

81 (3S)-3-(4-((3-(4- Methoxypyridin-3- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

82 (3S)-3-(4-((3-(6-Methoxy-4- methylpyridin-3- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

83 (3S)-3-(4-((3-(3- Methoxypyridin-4- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

84 (3S)-3-(4-((3-(5-Methoxy-3- methylpyridin-2- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

85 (3R)-3-[6-[[3-(2- Methylphenyl)benzo[b]thiophen-5-yl]methoxy]pyridin-3-yl] hex-4-ynoic acid

86 (3S)-3-[4-[([3-[2-Methyl-4- (tetrahydrofuran-3-yloxy)phenyl]-1-benzothiophen- 5-yl]oxy)methyl]phenyl] hex-4-ynoic acid

87 (3R)-3-(6-((3-(5-(2- Methoxyethoxy)-2- methylphenyl)benzo[b]thiophen-5- yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

88 (3R)-3-(6-((3-(3-(2- Methoxyethoxy)-2- methylphenyl)benzo[b]thiophen-5- yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

89 (3R)-3-(6-((3-(5-(2- Methoxyethoxy)-3- methylpyridin-2-yl)benzo[b]thiophen-5- yl)methoxy)pyridin-3-yl) hex-4-ynoic acid

90 (3R)-3-(6-((3-(2-Chloro-5- methylpyridin-4- yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4- ynoic acid

91 (3S)-3-(4-((3-(3- Methoxypyridin-2- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

92 (3R)-3-(6-((3-(5-(2- Methoxyethoxy)-2- methylpyridin-3-yl)benzo[b]thiophen-5- yl)methoxy)pyridine-3-yl) hex-4-ynoic acid

93 (3S)-3-(4-((3-(6-Chloro-3- methylpyridin-2- yl)benzo[b]thiophen-5-yl)methoxy)phenyl) hex-4-ynoic acid

94 (3S)-3-(4-((3-(6-Methoxy-3- methylpyridin-2- yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid

95 (3S)-3-(4-((3-(2-Methyl-4- (piperidin-4-ylmethyl)phenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)hex-4- ynoic acid

96 (3S)-3-(4-((3-(2-Methyl-4- (piperidin-4-yl)phenyl)benzo[b]thiophen-5- yl)methoxy)phenyl)hex-4-ynoic acid

97 3-(4-((3-(2- Methylphenyl)benzo[b]thiophen- 5-yl)methoxy)phenyl)hex-4-ynoic acid

98 (3R)-3-[4-[[3-(2- Methylphenyl)benzo[b]thiophen- 5-yl]methoxy]phenyl]hex-4-ynoic acid

In a further embodiment, the invention is directed a compositioncomprising (a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein theGPR40 agonist is a compound of Formula (I)

selected from the group consisting of

-   Cpd 1,    3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]propanoic    acid;-   Cpd 2,    (3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 3,    (3S)-3-[4-[[3-[4-[(4-Hydroxy-1,1-dioxo-thian-4-yl)methoxy]-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 4, (3S)-3-[4-[[3-[2-Methyl-4-(3-methyl    sulfonylpropoxy)phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 5,    (3S)-3-[4-[[3-[4-(1,1-Dioxo-1,4-thiazinane-4-carbonyl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 6,    (3S)-3-[4-[[3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 7,    (3S)-3-[4-[[3-(4-Hydroxy-2-methyl-phenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 8,    (3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 9,    (3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)oxy-2-methyl-phenyl]-2-methyl-benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 10,    (3S)-3-[4-[[3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;-   Cpd 11,    (3S)-3-(4-((3-(4-(2-(1-Hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 12,    (3S)-3-(4-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 13,    (3S)-3-(4-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 14,    (3S)-3-(4-((3-(2-Methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 15,    (3S)-3-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 16,    (3S)-3-(4-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 17,    (3S)-3-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 18,    (3S)-3-(4-((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 19,    (3S)-3-(4-((3-(2-Chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)    hex-4-ynoic acid;-   Cpd 20,    (3S)-3-(4-((3-(2-Bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)    hex-4-ynoic acid;-   Cpd 21,    (3S)-3-(4-((3-(2-(Trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 22,    (3S)-3-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)    hex-4-ynoic acid;-   Cpd 23,    (3S)-3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)    hex-4-ynoic acid;-   Cpd 24,    (3S)-3-(4-(((3-(2-Methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)    hex-4-ynoic acid;-   Cpd 25,    (3S)-3-(4-(((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic    acid;-   Cpd 26,    (3S)-3-(4-(((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic    acid;-   Cpd 27,    (3S)-3-(4-(((3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)    hex-4-ynoic acid;-   Cpd 28,    2-(1-(4-((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic    acid;-   Cpd 29,    2-(1-(4-((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic    acid;-   Cpd 30,    2-(3-Oxo-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic    acid;-   Cpd 31,    2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic    acid;-   Cpd 32,    2-(1-(4-((3-(4-(2-Ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic    acid;-   Cpd 33,    2-(1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic    acid;-   Cpd 34,    2-(1-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic    acid;-   Cpd 35,    2-((1r,3r)-3-Hydroxy-1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic    acid;-   Cpd 36,    2-((1r,3r)-1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-hydroxycyclobutyl)acetic    acid;-   Cpd 37,    2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic    acid;-   Cpd 38,    2-(1-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic    acid;-   Cpd 39,    2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic    acid;-   Cpd 40,    2-(1-(4-((3-(4-(1,1-Dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic    acid;-   Cpd 41,    (3S)-3-(4-((3-(2-Methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 42,    (3S)-3-(4-((3-(2-Methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 43,    (3S)-3-(4-((3-(2-Methyl-5-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 44,    (3S)-3-(4-((3-(2-Methyl-6-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 45,    3-(6-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)    hex-4-ynoic acid;-   Cpd 46,    3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 47,    3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 48,    (3S)-3-(4-((3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 49,    (3S)-3-(4-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 50,    (3S)-3-(4-((3-(6-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 51,    (3S)-3-(4-((3-(6-(2-Methoxyethoxy)-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 52,    (3S)-3-(4-((3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 53,    3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)propanoic    acid;-   Cpd 54,    (3S)-3-[4-[([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic    acid;-   Cpd 55,    (3S)-3-[4-[([3-[4-(2,3-Dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic    acid;-   Cpd 56,    (3S)-3-(4-[[(3-[2-Methyl-4-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoic    acid;-   Cpd 57,    (3S)-3-[4-[([3-[2-Methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic    acid;-   Cpd 58,    (3S)-3-[4-[([3-[4-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic    acid;-   Cpd 59,    (3S)-3-{4-[((3-{4-[(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)oxy)methyl]phenyl}hex-4-ynoic    acid;-   Cpd 60,    (3S)-3-(4-(((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic    acid;-   Cpd 61,    3-[6-([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoic    acid;-   Cpd 62,    3-(6-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 63,    3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 64,    3-(6-((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 65,    (3S)-3-[4-([3-[5-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic    acid;-   Cpd 66,    (3S)-3-[4-([3-[2-(2-Methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic    acid;-   Cpd 67,    (3S)-3-[4-([3-[3-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic    acid;-   Cpd 68,    (3S)-3-[4-([3-[2-(2-Methoxyethoxy)phenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic    acid;-   Cpd 69,    (3S)-3-(4-[[3-(2-Methanesulfonylphenyl)-1-benzothiophen-6-yl]methoxy]phenyl)hex-4-ynoic    acid;-   Cpd 70,    (3S)-3-(6-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid-   Cpd 71,    (3R)-3-(6-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid-   Cpd 72,    (3S)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid-   Cpd 73,    (3R)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid-   Cpd 74,    (3S)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 75,    (3R)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 76, (3S)-3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)    benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;-   Cpd 77, (3R)-3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)    benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;-   Cpd 78,    (3S)-3-(4-((3-(2-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 79,    (3S)-3-(4-((3-(2-Methoxyphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 80,    (3S)-3-(4-((3-(6-Methoxy-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 81,    (3S)-3-(4-((3-(4-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 82,    (3S)-3-(4-((3-(6-Methoxy-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 83,    (3S)-3-(4-((3-(3-Methoxypyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 84,    (3S)-3-(4-((3-(5-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 85,    (3R)-3-[6-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]pyridin-3-yl]hex-4-ynoic    acid;-   Cpd 86,    (3S)-3-[4-[([3-[2-Methyl-4-(tetrahydrofuran-3-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic    acid;-   Cpd 87, (3R)-3-(6-((3-(5-(2-Methoxyethoxy)-2-methylphenyl)    benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;-   Cpd 88, (3R)-3-(6-((3-(3-(2-Methoxyethoxy)-2-methylphenyl)    benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;-   Cpd 89,    (3R)-3-(6-((3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 90,    (3R)-3-(6-((3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic    acid;-   Cpd 91,    (3S)-3-(4-((3-(3-Methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 92,    (3R)-3-(6-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)pyridine-3-yl)hex-4-ynoic    acid;-   Cpd 93,    (3S)-3-(4-((3-(6-Chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 94,    (3S)-3-(4-((3-(6-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 95,    (3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 96,    (3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 97,    3-(4-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic    acid;-   Cpd 98,    (3R)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic    acid;    or a pharmaceutically acceptable salt form thereof.

Embodiments of the present invention include an SGLT2 inhibitor selectedfrom canagliflozin, dapagliflozin, empagliflozin, ipragliflozin,luseogliflozin, tofogliflozin, bexagliflozin, ertugliflozin, ISIS388626, remogliflozin, sergliflozin etabonate, or sotagliflozin. In apreferred embodiment, the present invention includes an SGLT2 inhibitorselected from canagliflozin, dapagliflozin, empagliflozin oripragliflozin. In a further preferred embodiment, the SGLT2 inhibitor iscanagliflozin.

For use in medicine, salts of compounds of the present invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds of the presentinventionor of their pharmaceutically acceptable salt forms thereof.Suitable pharmaceutically acceptable salts of compounds of the presentinvention include acid addition salts that can, for example, be formedby mixing a solution of the compound with a solution of apharmaceutically acceptable acid such as, hydrochloric acid, sulfuricacid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoicacid, citric acid, tartaric acid, carbonic acid or phosphoric acid.Furthermore, where the compounds of the present invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts such as, sodium or potassium salts; alkalineearth metal salts such as, calcium or magnesium salts; and salts formedwith suitable organic ligands such as, quaternary ammonium salts. Thus,representative pharmaceutically acceptable salts include acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide, and valerate.

Representative acids and bases that may be used in the preparation ofpharmaceutically acceptable salts include acids including acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid,malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and bases including ammonia, L-arginine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine,diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine, tromethamine, and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds ofthe present invention. In general, such prodrugs will be functionalderivatives of the compounds that are readily convertible in vivo intothe required compound. Thus, in the methods of treating or preventingembodiments of the present invention, the term “administering”encompasses the treatment or prevention of the various diseases,conditions, syndromes and disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to a patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to embodiments of this invention have atleast one chiral center, they may accordingly exist as enantiomers.Where the compounds possess two or more chiral centers, they mayadditionally exist as diastereomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofthe present invention. Furthermore, some of the crystalline forms forthe compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compoundsmay form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention. The skilled artisan will understand thatthe term compound as used herein, is meant to include solvated compoundsof the present invention.

Where the processes for the preparation of the compounds according tocertain embodiments of the invention give rise to mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as, preparative chromatography. The compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as, the formation of diastereomeric pairs by saltformation with an optically active acid such as,(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column.

One embodiment of the present invention is directed to a composition,including a pharmaceutical composition, comprising, consisting of,and/or consisting essentially of the (+)-enantiomer of a compound ofFormula (I) wherein said composition is substantially free from the(−)-isomer of said compound. In the present context, substantially freemeans less than about 25%, preferably less than about 10%, morepreferably less than about 5%, even more preferably less than about 2%and even more preferably less than about 1% of the (−)-isomer calculatedas

${\% \mspace{14mu} ( + )\mspace{11mu} ­\mspace{11mu} {enantiomer}} = {\frac{( {{{mass}( + )}\mspace{11mu} ­\mspace{11mu} {enantiomer}} )}{( {{{mass}( + )}\mspace{11mu} ­\mspace{11mu} {enantiomer}} ) + ( {{{mass}( - )}\mspace{11mu} ­\mspace{11mu} {enantiomer}} )} \times 100.}$

Another embodiment of the present invention is a composition, includinga pharmaceutical composition, comprising, consisting of, and consistingessentially of the (−)-enantiomer of a compound of Formula (I) whereinsaid composition is substantially free from the (+)-isomer of saidcompound. In the present context, substantially free from means lessthan about 25%, preferably less than about 10%, more preferably lessthan about 5%, even more preferably less than about 2% and even morepreferably less than about 1% of the (+)-isomer calculated as

${\% \mspace{14mu} ( + )\mspace{11mu} ­\mspace{11mu} {enantiomer}} = {\frac{( {{{mass}( - )}\mspace{11mu} ­\mspace{11mu} {enantiomer}} )}{( {{{mass}( + )}\mspace{11mu} ­\mspace{11mu} {enantiomer}} ) + ( {{{mass}( - )}\mspace{11mu} ­\mspace{11mu} {enantiomer}} )} \times 100.}$

During any of the processes for preparation of the compounds of thevarious embodiments of the present invention, it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups such as those described in Protective Groups inOrganic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973;T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, 1991; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known from the art.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds ofFormula (I) and at least one pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and/or pharmaceuticallyacceptable diluent.

By way of example, in the pharmaceutical compositions of embodiments ofthe present invention, the compounds of Formula (I) may be admixed withany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms such as, tablets or capsules, containing thecompounds of the present invention may be administered in at least onedosage form at a time, as appropriate. It is also possible to administerthe compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may beadministered include elixirs, solutions, syrups, and suspensions; eachoptionally containing flavoring agents and coloring agents.

Alternatively, compounds of Formula (I) can be administered byinhalation (intratracheal or intranasal) or in the form of a suppositoryor pessary, or they may be applied topically in the form of a lotion,solution, cream, ointment or dusting powder. For example, they can beincorporated into a cream comprising, consisting of, and/or consistingessentially of an aqueous emulsion of polyethylene glycols or liquidparaffin. They can also be incorporated, at a concentration of betweenabout 1% and about 10% by weight of the cream, into an ointmentcomprising, consisting of, and/or consisting essentially of a wax orsoft paraffin base together with any stabilizers and preservatives asmay be required. An alternative means of administration includestransdermal administration by using a skin or transdermal patch.

The pharmaceutical compositions of the present invention (as well as thecompounds of the present invention alone) can also be injectedparenterally, for example, intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally, or intrathecally. Inthis case, the compositions will also include at least one of a suitablecarrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of thepresent invention are best used in the form of a sterile aqueoussolution that may contain other substances, for example, enough saltsand monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositionsof the present invention may be administered in the form of tablets orlozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing atleast one of the compounds of Formula (I) as the active ingredient canbe prepared by mixing the compound(s) with a pharmaceutically acceptablecarrier, a pharmaceutically acceptable diluent, and/or apharmaceutically acceptable excipient according to conventionalpharmaceutical compounding techniques. The carrier, excipient, anddiluent may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral, etc.). Thus, for liquidoral preparations such as, suspensions, syrups, elixirs and solutions,suitable carriers, excipients and diluents include water, glycols, oils,alcohols, flavoring agents, preservatives, stabilizers, coloring agentsand the like; for solid oral preparations such as, powders, capsules,and tablets, suitable carriers, excipients and diluents includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations also may beoptionally coated with substances such as, sugars, or be entericallycoated so as to modulate the major site of absorption anddisintegration. For parenteral administration, the carrier, excipientand diluent will usually include sterile water, and other ingredientsmay be added to increase solubility and preservation of the composition.Injectable suspensions or solutions may also be prepared utilizingaqueous carriers along with appropriate additives such as, solubilizersand preservatives.

A therapeutically effective amount of a compound of Formula (I) or apharmaceutical composition thereof includes a dose range from about 0.1mg to about 3000 mg, or any particular amount or range therein, inparticular from about 1 mg to about 1000 mg, or any particular amount orrange therein, or, more particularly, from about 10 mg to about 500 mg,or any particular amount or range therein, of active ingredient in aregimen of about 1 to about 4 times per day for an average (70 kg)human; although, it is apparent to one skilled in the art that thetherapeutically effective amount for a compound of Formula (I) will varyas will the diseases, syndromes, conditions, and disorders beingtreated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 1.0, about 10, about50, about 100, about 150, about 200, about 250, and about 500 milligramsof a compound of Formula (I).

Advantageously, a compound of Formula (I) may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three and four times daily.

Optimal dosages of a compound of Formula (I) to be administered may bereadily determined and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease, syndrome, condition or disorder. Inaddition, factors associated with the particular subject being treated,including subject gender, age, weight, diet and time of administration,will result in the need to adjust the dose to achieve an appropriatetherapeutic level and desired therapeutic effect. The above dosages arethus exemplary of the average case. There can be, of course, individualinstances wherein higher or lower dosage ranges are merited, and suchare within the scope of this invention.

Compounds of Formula (I) may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of a compound ofFormula (I) is required for a subject in need thereof.

One embodiment of the present invention is directed to a pharmaceuticalcomposition comprising (a)3-(4-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (compound 97) and (b) an SGLT2 inhibitor selected from the groupconsisting of canagliflozin, dapagliflozin, empagliflozin,ipragliflozin, luseogliflozin, tofogliflozin, bexagliflozin,ertugliflozin, ISIS 388626, remogliflozin, sergliflozin etabonate, andsotagliflozin; and at least one of a pharmaceutically acceptablecarrier, a pharmaceutically acceptable excipient, and a pharmaceuticallyacceptable diluent.

Another embodiment of the present invention is directed to apharmaceutical composition comprising (a)3-(4-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (compound 97) and (b) the SGLT2 inhibitor canagliflozin; and atleast one of a pharmaceutically acceptable carrier, a pharmaceuticallyacceptable excipient, and a pharmaceutically acceptable diluent.

Another embodiment of the present invention is directed to apharmaceutical composition comprising (a)(3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (compound 2) and (b) an SGLT2 inhibitor selected from the groupconsisting of canagliflozin, dapagliflozin, empagliflozin,ipragliflozin, luseogliflozin, tofogliflozin, bexagliflozin,ertugliflozin, ISIS 388626, remogliflozin, sergliflozin etabonate, andsotagliflozin; and at least one of a pharmaceutically acceptablecarrier, a pharmaceutically acceptable excipient, and a pharmaceuticallyacceptable diluent.

Another embodiment of the present invention is directed to apharmaceutical composition comprising (a)(3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (compound 2) and (b) the SGLT2 inhibitor canagliflozin; and atleast one of a pharmaceutically acceptable carrier, a pharmaceuticallyacceptable excipient, and a pharmaceutically acceptable diluent.

In another embodiment, the present invention is directed to acomposition comprising (a) a GPR40 agonist of Formula (I) and (b) anSGLT2 inhibitor; for use in the treatment of a disorder affected by themodulation of GPR40 and SGLT2, selected from the group consisting ofType II diabetes mellitus, hyperglycemia, hyperinsulinemia, obesity,obesity-related disorders, impaired glucose tolerance, insulinresistance, hypertriglyceridemia, metabolic syndrome, diabeticcomplications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema.

In another embodiment, the present invention is directed to acomposition comprising (a) a GPR40 agonist of Formula (I) and (b) anSGLT2 inhibitor, for use in the treatment of Type 2 diabetes mellitus.

General Synthetic Methods

Representative compounds of Formula (I) of the present invention can besynthesized in accordance with the general synthetic methods describedbelow and illustrated in the schemes and examples that follow. Since theschemes are an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions described in theschemes and examples. The various starting materials used in the schemesand examples are commercially available or may be prepared by methodswell within the skill of persons versed in the art. The variables are asdefined herein.

Abbreviations used in the instant specification, particularly theschemes and examples, are as follows:

-   -   ADDP azodicarboxylic acid dipiperidide    -   aq aqueous    -   9-BBN 9-borabicyclo[3,3,1]nonane    -   BINAP 2,2′-bis[1,1-diphenylphosphino]-1,1′-binaphthalene    -   Boc tert-butoxycarbonyl    -   CDI 1,1′-carbonyldiimidazole    -   CyJohnPhos (2-biphenyl)dicyclohexylphosphine    -   DBAD di-tert-butyl azodicarboxylate    -   DCE 1,2-dichloroethane    -   DCM dichloromethane    -   DEA diethylamine    -   DEAD diethyl azodicarboxylate    -   DIAD diisopropyl azodicarboxylate    -   DIBAL-H diisobutylaluminum hydride    -   DIEA diisopropylethylamine    -   DME ethylene glycol dimethyl ether    -   DMF dimethylformamide    -   DMSO methyl sulfoxide    -   EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide    -   EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   Et ethyl    -   EtOAc ethyl acetate    -   h hour(s)    -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate)    -   HCl hydrochloric acid    -   HPLC high performance liquid chromatography    -   LAH lithium aluminum hydride    -   LCAP liquid chromatography area percent    -   LCMS high pressure liquid chroatography with mass spectrometer    -   mCPBA 3-chloroperbenzoic acid    -   Me methyl    -   MeCN acetonitrile    -   MeOH methyl alcohol    -   mg milligram    -   MOM methoxymethyl    -   MTBE methyl t-butyl ether    -   NBS N-bromosuccinimide    -   NCS N-chlorosuccinimide    -   NIS N-iodosuccinimide    -   NMP N-methyl-2-pyrrolidone    -   N,N-DMA N, N-dimethylacetamide    -   PCC pyridinium chlorochromate    -   PDC pyridinium dichromate    -   PdCl₂(dppf).CH₂Cl₂        1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride        dichloromethane complex)    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)    -   PPTS pyridine p-toluenesulfonate    -   P(o-tol)₃ tri(o-tolyl)phosphine    -   rt room temperature    -   RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl    -   satd. saturated    -   SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl    -   TBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   Tf₂O triflic anhydride    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   THP tetrahydropyranyl        Scheme A illustrates a method for the preparation of certain        compounds of Formula (I) of the present

Certain compounds of Formula (I-A) may be synthesized as outlined by thegeneral synthetic route illustrated in Scheme A. Treatment of5-hydroxymethylbenzothiophene II with a halogenating reagent such asNBS, NIS or in a suitable solvent such as DCM, DCE, CCl₄, THF, dioxane,DMF and the like or with Br₂ in HOAc, at a temperature preferablybetween 0 and 50° C. can provide the 3-halogenated benzothiophene IIIwherein X is bromine or iodine. Halogenated benzothiophene III may bereacted with a compound of formula (R₃)(R₅)W-M wherein R₃, R₅ and W areas defined herein, under suitable coupling conditions, to yield thecorresponding coupling product of formula IV. A compound of formula(R₃)(R₅)W-M is chosen wherein M may be (a) a boronic acid to form acompound of formula (R₃)(R₅)W—B(OH)₂; (b) a suitably selected boronicester such as pinacolatoboryl, neopentylglycolatoboryl, and the like;(c) a suitably selected trialkylstannyl such as tri(n-butyl)tin, and thelike; (d) a suitably selected trialkylsilyl such as triallylsilyl, andthe like; (e) a suitably selected aryldialkylsilyl such as2-(hydroxymethyl)phenyldimethylsilyl, and the like or (f) suitablyselected organo zinc reagents such as (R₃)(R₅)W—ZnX wherein X is ahalogen such as Cl, Br or I.

For example, a compound of formula (R₃)(R₅)W-M where M is preferably—B(OH)₂ or a suitably selected W-substituted boronic ester may bereacted with a compound of formula III under Suzuki coupling conditions,more particularly in the presence of a suitably selected palladiumcatalyst such as palladium (II) acetate, palladium (II) chloride,bis(acetonitrile)-dichloro-palladium(II), allylpalladium (II) chloridedimer, tris(dibenzylidineacetone) dipalladium (0) (Pd₂(dba)₃),2-(di-tert-butylphosphino)biphenyl,dichloro-bis(di-tert-butylphenylphosphine)-palladium (II),[1,1′-bis-(diphenylphosphino)-ferrocene]-palladium (II) dichloridedichloromethane adduct (PdCl₂(dppf).DCM), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), (1,1′-bis(di-tert-butylphosphino)ferrocenepalladium (II) chloride, and the like; optionally in the presence of asuitably selected ligand such as triphenylphosphine,tri-o-tolylphosphine, tributylphosphine, tri(tert-butyl)-phosphine,tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)-ferrocene,2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl, S-Phos,Ru-Phos, bis[2-(diphenyl-phosphino)phenyl] ether,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, tris(2-furyl)phosphine,1-butyl-3-methylimidazolium hexafluorophosphate, and the like; in thepresence of a suitably selected inorganic base such as cesium carbonate,potassium carbonate, sodium carbonate, cesium fluoride, potassiumfluoride, tetrabutylammonium fluoride, potassium tert-butoxide, sodiumtert-butoxide, sodium hydroxide, sodium bicarbonate; potassium phosphateor preferably sodium carbonate; in a suitably selected solvent such asethanol, THF, DMF, toluene, benzene, DME, H₂O, 1,4-dioxane, and thelike, or a combination thereof; at a temperature ranging from about rtto about 180° C.

Compounds of formula IV may be reacted under Mitsunobu conditions (for areview, see: Mitsunobu, O. Synthesis (1981), 1-28) with compounds offormula VI, wherein R₁ and R₆ are as defined herein, in the presence oftriphenylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, or aresin-bound triphenylphosphine equivalent, such as PS—PPh₃ and an azidocoupling reagent such as DIAD, ADDP, DBAD or DEAD and the like, in anorganic solvent such as THF, MeCN, toluene, N,N-DMA, and the like, at atemperature preferably between 25-100° C., to yield compounds of formulaVII.

Alternatively, the alcoholic function of compounds of formula IV may beconverted to suitable leaving groups (LG) such as Cl, Br, I, tosylate,mesylate, nosylate and the like, (as described in: March, J. AdvancedOrganic Chemistry. Reactions, Mechanisms and Structure, 2^(nd) ed.;McGraw-Hill Co.: New York, 1977; pp 326) as illustrated by compounds offormula V, which may then react with a compound of formula VI in thepresence of a suitable base to provide a compound of formula VII. Forexample, treatment of a compound of formula IV with a halogenatingreactant such as oxalyl chloride, oxalyl bromide, thionyl chloride,thionyl bromide, Ph₃P.Br₂, PBr₃ and the like, or with sulfonyl halidessuch as tosyl chloride, mesyl chloride, nosyl chloride and the like; inthe presence of a base such as K₂CO₃, Cs₂CO₃, KOH, NaH, and the like, ina solvent such as NMP, DMF, THF, and the like, at a temperaturepreferably between 25-150° C. may provide a compound of formula V.Reaction of a compound of formula V may be reacted with a compound offormula VI in the presence of a suitable base such as K₂CO₃, Cs₂CO₃,KOH, NaH, and the like, in a solvent such as NMP, DMF, THF, and thelike, at a temperature preferably between 25-150° C. to provide acompound of formula VII.

Hydrolysis of the ester functionality of a compound of formula VII maybe effected under a variety of conditions to provide a compound offormula (I-A) (such as described in T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) ed.; John Wiley & Sons,Inc.: New York, 1999). For example, treatment of a compound of formulaVII with a base such as NaOH, LiOH, KOH, CsOH and the like, in a solventsuch as THF, EtOH, MeOH, dioxane and water and the like, or mixturesthereof, at a temperature between 25° C. and 100° C. may provide acompound of formula (I-A). The preferred method for this transformationincludes the treatment of a compound of formula VII with an aqueous basesuch as NaOH or LiOH, in a mixed solvent such as THF/MeOH, at about roomtemperature.

It should be understood that in certain compounds of formulas(R₃)(R₅)W-M, IV, V, or VII, R₃ may contain functionalities that mayoptionally bear a suitable functional protecting group (P) (such asthose described in Protective Groups in Organic Chemistry, J. F. W.McOmie, Ed.; Plenum Press: 1973; and T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) ed.; John Wiley & Sons,Inc.: New York, 1999). In such cases where the R₃ is substituted withone or more amino groups, suitable protecting groups such as Boc, Cbz,and the like may be incorporated, which may be deprotected underappropriate conditions known to those skilled in the art to afford acompound of Formula (I-A) of the present invention. For example,Boc-protected amines may be deprotected under acidic conditions usingreagents such as HCl, TFA, and the like. Likewise, Cbz-protected aminesmay be deprotected under acidic conditions or hydrogenolysis. In thecase where R₃ is substituted with carboxyl groups, suitable protectinggroups such as methyl, ethyl and t-butyl esters and the like may beincorporated, which may be deprotected under acidic conditions such asHCl, TFA and the like. In the case where R₃ is substituted with hydroxylgroups, suitable protecting groups such as MOM, THP, t-butyl ethers,acetonides (for 1,2-dihydroxylated substituents) and the like may beincorporated, which may be deprotected under acidic conditions such asHCl, TFA and the like. The unmasked functionalities generated bydeprotection may be subjected to further chemical transformationsaccording to methods known in the art, to provide additional derivativesof Formula (I-A).

In certain cases, a compound of formula IV of the present invention maybe advantageously prepared by an alternative cross-coupling strategy, asillustrated in Scheme B.

Under Suzuki coupling conditions as previously described for Scheme A, acompound of formula III may be reacted with bis(pinacolato)diboron toprovide the corresponding borolane of formula VIII. A compound offormula VIII may, in turn, be reacted with an aromatic halide of formula(R₃)(R₅)W—X, wherein (R₃)(R₅)W and X are as defined in Scheme A, toprovide a compound of formula IV directly. In certain cases, thiscoupling reaction affords the corresponding aldehydic compound offormula IX, which upon treatment with a suitable reducing agent (asdescribed in: Larock, R. C. Comprehensive Organic Transformations. AGuide to Functional Group Preparations, 2^(nd) ed.; Wiley-VCH: New York,1999; pp 61), such as NaBH₄, LAH, B₂H₆, DIBAL-H, NaCNBH₃, AlH₃,LiAlH(O-t-Bu)₃, KBH(O-i-Pr)₃, and the like, preferably NaBH₄ or B₂H₆, ina solvent such as THF, ether, dioxane, MeOH, EtOH and the like, at atemperature preferably between 0-75° C., may provide an alcohol offormula IV.

Certain compounds of formula IV of the present invention in which R₃ is—OR_(4c) can be prepared as illustrated in Scheme C. As defined herein,R_(4c) is R₄ wherein the hydroxy-substituted R₄ substituents aresuitably protected with a conventional hydroxy protecting group.

Treatment of a compound of formula III with a compound of formula(R_(4c)O)(R₅)W-M, where W, R₅, and M are as defined in Scheme A, undercoupling conditions previously described may provide a compound offormula IVa directly. Alternatively, a compound of formula III may bereacted with a compound of formula (HO)(R₅)W_(c)-M wherein W_(c) isphenyl, and M is preferably a boronic acid or boronic ester, undersuitable coupling conditions as previously described, to provide thecorresponding coupling product of formula X. Alkylation of a compound offormula X with a compound of formula R_(4c)-LG, where LG is a suitableleaving group as previously described, in the presence of a base such asK₂CO₃, Cs₂CO₃, KOH, NaH, and the like, in a solvent such as NMP, DMF,THF, and the like, at a temperature preferably between 25-150° C. mayprovide a compound of formula IVa. Alternatively, a compound of formulaX may be alkylated by reaction with an epoxide of formula XI, whereinR_(c) is hydrogen and R_(4c1) is defined as C₁₋₆alkyl, C₃₋₇cycloalkyl,or C₁₋₃alkoxy(C₁₋₈)alkyl, to provide a compound of formula IVc.Similarly, a compound of formula X may be alkylated by reaction with anepoxide of formula XI, wherein R_(c) and R_(4c1) may be taken togetherto form a spirofused ring selected from the group consisting ofC₄₋₇spirocycloalkyl, spirofused1,1-dioxido-tetrahydro-2H-thiopyran-4-yl, and spirofusedtetrahydro-2H-pyran-4-yl, to provide additional compounds of formulaIVc. The reaction with an epoxide of formula XI is preferably carriedout in the presence of a base such as K₂CO₃, Cs₂CO₃, KOH, and the like,in a solvent such as NMP, DMF, THF, and the like, at a temperaturepreferably between about 25 and about 125° C.

Alternatively, certain compounds of formula IV of the present inventionin which R₃ is —OR_(4d) and R₅ is Me or CF₃ may be prepared asillustrated in Scheme D. As defined herein, R_(4d) is R₄ wherein thehydroxy-substituted R₄ substituents are suitably protected with aconventional hydroxy protecting group.

Alkylation of a phenolic compound of formula XII with a compound offormula R_(4d)-LG, where LG is a suitable leaving group as previouslydescribed, in the presence of a base such as K₂CO₃, Cs₂CO₃, KOH, NaH,and the like, in a solvent such as NMP, DMF, THF, and the like, at atemperature preferably between about 25° C. to about 150° C. may providea compound of formula XIII Treatment of a compound of formula XIII withbis(pinacolato)diboron under Suzuki coupling conditions, as defined inScheme A, may provide the corresponding borolane of formula XIV. Aborolane of formula XIV may be reacted with a benzothiophene aldehyde offormula XV under Suzuki coupling conditions, as defined in Scheme A, toprovide an arylated benzothiophene aldehyde of formula XVI, which inturn may be reduced upon treatment with a suitably selected reducingagent (as described in Larock, R. C. Comprehensive OrganicTransformations. A Guide to Functional Group Preparations, 2^(nd) ed.;Wiley-VCH: New York, 1999; pp 61), such as NaBH₄, LAH, B₂H₆, DIBAL-H,NaCNBH₃, AlH₃, LiAlH(O-t-Bu)₃, KBH(O-i-Pr)₃, and the like; preferablyNaBH₄ or B₂H₆, in a solvent such as THF, ether, dioxane, MeOH, EtOH andthe like, at a temperature preferably between about 0 to about 75° C.,to provide the corresponding benzylic alcohol of formula IVd.

In addition, certain compounds of formula IVe of the present inventionin which R₃ is 1,1-dioxo-1,4-thiazinane-4-ylcarbonyl can be prepared asillustrated in Scheme E.

Compounds of formula III may be reacted with a compound of formula(R₅)(R₃)W-M wherein (R₅)(R₃)W— is a methoxycarbonyl-substituted phenylor pyridyl ring, and M is preferably a boronic acid or boronic ester,under suitable coupling conditions as previously described, to providethe corresponding coupling product of formula XV. Hydrolysis of theester functionality of compounds of formula XV can be effected under avariety of conditions, as previously described. The preferred method forthis transformation includes the treatment of compounds of formula XVwith an aqueous base such as NaOH or LiOH in a mixed solvent such asTHF/MeOH at about room temperature to provide compounds of formula XVI.Reaction of benzoic acid XVI and thiomorpholine 1,1-dioxide withconventional coupling agents (M. Bodansky and A. Bodansky, The Practiceof Peptide Synthesis, Springer-Verlag: New York, 1984) such as EDCI,CDI, DCC, HATU, HBTU, TBTU, and the like in organic solvents such asDCM, THF, DMF, NMP, N,N-DMA, DMSO, and the like, at ambient temperaturemay provide the corresponding carboxamide of Formula IVe.

Certain compounds of formula VII of the present invention in which R₃ is—OR₄ may be prepared as illustrated in Scheme F.

A compound of formula III may be reacted with a compound of formula VIdirectly under Mitsunobu conditions, as defined in Scheme A to provide acompound of formula XX. Alternatively, a compound of formula III may beconverted to a compound of formula XIX, wherein LG is a suitable leavinggroup as previously described, and reacted with a phenol of formula VIin the presence of a suitable base as previously described to provide acompound of formula XX. Reaction of a compound of formula XX with acompound of formula (R₅)(R₃)W-M, using the methods described in SchemeA, provides a compound of formula VII. In instances wherein R₃ ishydroxy and W_(f) is phenyl, this reaction provides a compound offormula XXI. A compound of formula XXI may be reacted under Mitsunobuconditions as previously described with a compound of formula R₄OH, ormay be reacted with a compound of formula R₄-LG in the presence of asuitable base as previously described, to provide a compound of formulaVIIa. Alternatively, a compound of formula XX may be reacted with acompound of formula (R₄O)(R₅)W-M to provide a compound of formula VIIadirectly.

Certain compounds of Formula (I) of the present invention wherein A is—OCH₂— may be prepared as illustrated in Scheme G.

A hydroxybenzothiophene of formula XXII may be transformed to a compoundof formula XXIII, wherein the phenolic group bears a suitable functionalprotecting group (P). Suitable protecting groups including ethers suchas THP, MOM, SEM, TBDMS and the like, silyl ethers such as TBDMS and thelike, or esters such as acetate, benzoate, pivaloate and the like may beincorporated, which are stable to halogenation conditions.

Halogenation of a compound of formula XXIII provides a compound offormula XXIV, which may be deprotected under appropriate conditionsknown to those skilled in the art to afford a compound of Formula XXV. Aphenol of formula VI may be homologated to the corresponding benzylalcohol of formula XXVII through the intermediacy of a triflate offormula XXVI. Thus, a triflate of formula XXVI may undergopalladium-catalyzed direct hydroxymethylation with potassiumacetoxymethyltrifluoroborate following the conditions described by Murai(Murai, N. et al., Org. Lett., 2012, 14, 1278-1281) to provide abenzylic alcohol of formula XXVII. A compound of formula XXVII may bereacted with a compound of formula XXV directly under Mitsunobuconditions, as defined in Scheme A to provide a compound of formulaXXIX. Alternatively, a compound of formula XXVII may be converted to acompound of formula XXVIII, wherein LG is a suitable leaving group aspreviously described, and reacted with a phenol of formula XXV in thepresence of a suitable base as previously described, to provide acompound of formula XXIX. A compound of formula XXIX may be reacted witha compound of formula (R₅)(R₃)W-M as defined in Scheme A, wherein M ispreferably a boronic acid or boronic ester, under suitable couplingconditions as previously described, to provide the correspondingcoupling product of formula XXX. Subsequent ester hydrolysis, asdescribed in Scheme A affords a compound of Formula (I-G).

Compounds of formula VI, wherein R₁ taken with R₆ is 3-oxocyclobutanyl,may be prepared as illustrated in Scheme H.

Olefination of a 3-(hydroxy-protected)-cyclobutanone of formula XXXI,wherein P is a suitable protecting group as previously described, with aphosphoranylidene acetate of formula XXXII provides a carboxylidenylcyclobutane of formula XXXIII, which in turn may undergo ametal-catalyzed conjugate addition reaction with a boronic acid offormula H1 to provide a 3,3-disubstituted cyclobutane of formula XXXIV.Suitable metal catalyst systems includechloro(1,5-cyclooctadiene)rhodium(I) dimer, (Pd₂(dba)₃)′CHCl₃/PPh₃,RhCl₃/BINAP, acetylacetonatobis(ethylene)rhodium(I)/BINAP,Pd(OAc)₂/2,2′-bipyridine and the like, in solvents such as THF, dioxane,toluene, water and the like at a temperature between about 25° C. andabout 100° C. Subsequent deprotection under appropriate conditions knownto those skilled in the art, affords a hydroxycyclobutane of formulaXXXV, which may be oxidized to provide a cyclobutanone of formula VIh.Suitable oxidizing agents for carrying out this transformation include,but are not limited to SO₃-pyridine complex, PDC, PCC, MnO₂, DMSO/NCS,DMSO/Ac₂O, DMSO/DCI and the like, in a solvent such as DCM, DCE, DMSO,and the like, at a temperature between about −20° C. and about 80° C.

Certain compounds of Formula (I)-J1), wherein R₁ and R₆ are takentogether to form 3-hydroxycyclobutan-1-yl, may be prepared asillustrated in Scheme J.

Treatment of a compound of Formula (I-J) with a suitable reducing agentmay selectively reduce the ketone while in the presence of thecarboxylic acid functionality to provide a compound of formula (I-J1).In particular, a bulky reducing agent is known to effect astereoselective reduction of a ketone functionality to provide thecorresponding alcohol whose relative stereochemical configuration isdepicted in a compound of formula (I-J1). Suitable reducing agentspreferably include borohydride derivatives such as lithiumtri-sec-butylborohydride, potassium tri-sec-butylborohydride, and thelike; disiamylborane, 9-BBN, diisopinocampheylborane, and the like; in asolvent such as THF, ether, dioxane, toluene, and the like; at atemperature between about −70° C. and 50° C.

In certain cases, a compound of formula VII of the present invention maybe advantageously prepared by an alternative cross-coupling strategy, asillustrated in Scheme K.

Under Suzuki coupling conditions as previously described for Scheme D, acompound of formula XX may be converted to its corresponding boronateester of formula XXXVI, which, in turn, may be coupled to an aromatichalide of formula (R₅)(R₃)W—X, wherein (R₅) is Me and CF₃, and (R₃)W—Xare defined as in Scheme A, to provide a compound of formula VIIdirectly.

Certain compounds of formula IV of the present invention in which R₃ is—OR₄, may be prepared as illustrated in Scheme L.

A compound of formula XL may be coupled with a compound of formula(R₃)(R₅)W-M as previously defined herein to afford a compound of formulaXLI. Reduction of group T (ester or aldehyde) of a compound of formulaXLI using conventional methods known to one of skill in the art affordsthe corresponding methylalcohol of formula IV-L1. Alternatively, acompound of formula XL may be coupled with a compound of formulaHO(R₅)W₁-M wherein W₁ is phenyl to afford a compound of formula XLII.Subsequent reaction with a reagent of formula R₄-LG as previouslydescribed herein may afford a compound of formula XLIII Reduction ofgroup T (ester or aldehyde) of a compound of formula XLIII usingconventional methods known to one of skill in the art affords thecorresponding methylalcohol of formula IV-L2.

Specific Examples

General Procedure A:

A mixture of an arylbromide or aryliodide (1 mmol), an arylboronic acid,aryldioxaborolane or bis(pinacolato)diboron (1.5 mmol), a palladiumcatalyst (0.1 mmol) and K₂CO₃ (2-3 mmol) was placed in a reaction vesselwhich was then thoroughly purged with argon. Dioxane (3 mL) and water(1.5 mL) were added, and the mixture was stirred at 80-95° C. for 1 to 3h. After cooling to rt, the mixture was poured into EtOAc/H₂O (1:1, 10mL) and the aqueous layer was extracted with EtOAc (5 mL×2). Thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification of the resultant residue by silicagel chromatography (EtOAc/heptanes) afforded the desired biaryl product.

General Procedure B:

To a mixture of the alcohol (0.2 mmol) and the phenol (0.3 mmol) in dryTHF (1 mL) was added a mixture of the phosphine (Ph₃P, Bu₃P or t-Bu₃P;0.3 mmol) and the azidodicarboxylate (DEAD, DIAD, DBAD or ADDP; 0.3mmol), and the resultant solution was stirred under argon for 1-16 h.The mixture was then either worked up by an extractive process (ex.,quenching with satd. aq. NH₄Cl and extraction with EtOAc) orconcentrated directly under reduced pressure and the resultant residuewas purified by silica gel chromatography (EtOAc/heptanes) orEtOAc/petroleum ether to afford the desired phenolic ether.

General Procedure C:

To a solution of the ester (0.16 mmol) in THF (1 mL) and MeOH (0.5 mL)was added the hydroxide base (1N LiOH (aq) or 1N NaOH (aq)) (1 mL) andthe resultant mixture was stirred at rt for 1-3 h, or until hydrolysiswas complete.

The reaction was then acidified to pH 3-4 with either 1-2N HCl or 2Mcitric acid and poured into a 1:1 mixture of EtOAc/H₂O (10 mL). Theaqueous layer was extracted with EtOAc (5 mL×2) and the combined organicextract was dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was dissolved in DCM (1 mL) and the product wasprecipitated with heptanes to afford the pure carboxylic acid.

General Procedure D:

To an ice-cooled solution of the benzylic alcohol (0.22 mmol) in DCM (5mL) was added thionyl chloride (0.45 mmol) in drop-wise fashion. Afterstirring at 0-5° C. for 2 h, the reaction was quenched by the additionof water (˜10 mL) followed by DCM (50 mL). After partitioning the twophases, the organic layer was successively washed with water, satd.NaHCO₃ and brine, then dried (Na₂SO₄), filtered and concentrated toafford the corresponding benzylic chloride which was used withoutfurther purification.

General Procedure E:

A mixture of the benzylic chloride (0.11 mmol), the phenol (0.14 mmol)and Cs₂CO₃ (0.17 mmol) in MeCN (2 mL) was stirred at rt for 16 h. EtOAc(50 mL) was then added and the organic layer was successively washedwith water and brine, dried (Na₂SO₄), filtered and concentrated toafford the crude corresponding benzylic phenyl ether, which was purifiedby silica gel chromatography (EtOAc/heptanes).

General Procedure F:

To an ice-cooled solution of the benzothiophenyl aldehyde (1.02 mmol) inTHF (4 mL) and MeOH (0.5 mL) was added NaBH₄ (2.09 mmol) in aportion-wise fashion. After stirring for 30 min, the reaction wasquenched by the addition of satd. NH₄Cl (10 mL). The mixture wasextracted with EtOAc (3×20 mL) and the combined organic extracts weredried (Na₂SO₄) and concentrated under reduced pressure. Purification ofthe resultant residue by silica gel chromatography (0-20%EtOAc/petroleum ether) afforded the corresponding benzylic alcohol.

General Procedure G:

To a solution of the 2-(3-oxo-1-arylcyclobutyl)acetic acid (0.57 mmol)in THF (5 mL) was added lithium tri-sec-butylborohydride (1M in THF;1.14 mL, 1.14 mmol) and the resultant solution was stirred at 50° C. for20-30 min. 1N HCl was added to adjust the reaction solution pH to 5-6,and the mixture was then extracted with EtOAc (3×10 mL). The combinedorganic extracts were concentrated under reduced pressure and theresidue thus obtained was purified by silica gel chromatography (60%EtOAc in petroleum ether) to provide the anti2-((1r,3r)-3-hydroxy-1-(aryl)cyclobutyl)acetic acid.

Example 13-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]propanoicacid, Cpd 1

(A) To an ice-cooled solution of 5-hydroxymethylbenzothiophene (1.45 g;8.83 mmol) in THF (15 mL) was added NBS (1.73 g; 9.71 mmol) under anargon atmosphere. The resulting solution was allowed to warm to rt andstirring was continued for 3 h. The reaction was then concentrated underreduced pressure and the residue was purified by silica gelchromatography eluting with 0-20% EtOAc in heptanes to afford3-bromo-5-hydroxymethylbenzothiophene (968 mg, 45%) as a white solid. ¹HNMR (CDCl₃) δ: 7.78-7.88 (m, 2H), 7.46 (s, 1H), 7.43 (d, J=9.6 Hz, 1H),4.86 (d, J=5.8 Hz, 2H), 1.84 (t, J=5.8 Hz, 1H).

(B) 5-Hydroxymethyl-3-(2-methylphenyl)benzo[b]thiophene was preparedfrom 3-bromo-5-hydroxymethylbenzothiophene and 2-methylphenylboronicacid following General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as thepalladium catalyst. LC/MS: mass calcd. for C₁₆H₁₄OS: 254.35, found 277.1[M+Na]⁺.

(C) Methyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-propanoatewas prepared from 5-hydroxymethyl-3-(2-methylphenyl)benzo[b]-thiopheneand methyl 3-(4-hydroxyphenyl)propanoate following General Procedure Busing PPh₃ and DBAD. LC/MS: mass calcd. for C₂₆H₂₄O₃S: 416.54, found439.0 [M+Na]⁺.

(D)3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]propanoicacid (Cpd 1) was prepared from methyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-propanoatefollowing General Procedure C using LiOH as base and 2N HCl for reactionacidification. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, 1H), 7.42-7.50 (m,2H), 7.27-7.38 (m, 5H), 7.10 (d, J=8.59 Hz, 2H), 6.87 (d, J=8.59 Hz,2H), 5.08 (s, 2H), 2.89 (t, J=7.58 Hz, 2H), 2.57-2.69 (t, J=8.08 Hz,2H), 2.15 (s, 3H). LC/MS: mass calcd. for C₂₅H₂₂O₃S: 402.51, found 425.1[M+Na]⁺.

Example 2(3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 2

(A) (3S)-Methyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-hex-4-ynoatewas prepared from 5-hydroxymethyl-3-(2-methylphenyl)benzo[b]-thiophene(from Example 1) and (3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate(prepared as described in WO 2005086661) following General Procedure Busing PPh₃ and DBAD. LC/MS: mass calcd. for C₂₉H₂₆O₃S: 454.59, found455.1 [M]⁺, 477.0 [M+Na]⁺.

(B)(3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 2) was prepared from (3S)-methyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base 2N HCl for reactionacidification. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=9.09 Hz, 1H),7.41-7.50 (m, 2H), 7.27-7.38 (m, 7H), 6.89 (d, J=8.59 Hz, 2H), 5.08 (s,2H), 3.97-4.10 (m, 1H), 2.78 (dd, J=8.59, 15.66 Hz, 1H), 2.69 (dd,J=6.57, 15.66 Hz, 1H), 2.15 (s, 3H), 1.82 (d, J=2.02 Hz, 3H). LC/MS:mass calcd. for C₂₈H₂₄O₃S: 440.56, found 463.1 [M+Na]⁺.

Example 2a(3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 2

(A) To a cooled (−10° C. to 5° C.) solution of diisopropylamine (422 g,4.17 mol) in anhydrous THF (4.0 L) was added n-butyllithium (1517 mL of2.5 M in hexane, 3.79 mol) in drop-wise fashion over a period of 1.5 hunder an inert atmosphere of nitrogen. Upon completion of the addition,the reaction solution was stirred at −10° C. to 0° C. for an additional30 min, and then cooled to −78° C. A solution of5-bromobenzo[b]thiophene (670 g, 3.16 mol) and TMSCl (512 g, 4.74 mol)in THF (3.4 L) was added in drop-wise fashion and the resulting reactionmixture was stirred at −78° C. After completion of the reaction, asjudged by HPLC analysis, aq. NH₄Cl solution (5% w/w, 2 L) was added indrop-wise fashion into the reaction mixture while still under a nitrogenatmosphere and maintaining a temperature between −78° C. and −65° C. Themixture was then allowed to warm to rt and the aqueous phase wasremoved. Water (2 L) was added to the organic phase and after stirringat room temperature for 15 min, the aqueous phase was removed. Thecombined aqueous layers were back-extracted with EtOAc (2 L), and thecombined organic extracts were washed with sat.d aq. NaCl (2 L), dried(Na₂SO₄) and concentrated under reduced pressure to provide(5-bromobenzo[b]thiophen-2-yl)trimethylsilane (867 g, purity: 90.0 LCAP)as a light yellow liquid. ¹H NMR (CDCl₃) δ 7.93 (d, J=1.5 Hz, 1H), 7.72(d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 0.37 (s, 9H);LC/MS (APCI⁺) m/z 283.9 [M]⁺.

(B) To a cooled (−78° C.) solution of(5-bromobenzo[b]thiophen-2-yl)trimethylsilane (884 g, 3.10 mol) inanhydrous THF (4.4 L) under an inert atmosphere of nitrogen was addedn-butyllithium (1489 mL of 2.5 M in hexanes, 3.72 mol) in drop-wisefashion over a period of 50 min. After stirring at −78° C. for 20 min, asolution of DMF (271 g, 3.72 mol) in THF (1326 mL) was introduced indrop-wise fashion over a period of 1 h, and the resulting reactionmixture was stirred at −78° C. and monitored by HPLC. After completionof the reaction (20 min), MeOH (150 mL) was added in drop-wise fashionand the mixture was stirred for 15 min at −78° C. Aq. NH₄Cl solution (5%w/w, 2 L) was then added in drop-wise fashion into the reaction mixture,after which the mixture was allowed to warm to rt and the aqueous phasewas removed. Water (2 L) was added to the organic phase and afterstirring at room temperature for 15 min, the aqueous phase was removed.The combined aqueous layers were back-extracted with EtOAc (2 L), andthe combined organic extracts were washed with sat.d aq. NaCl (2 L),dried (Na₂SO₄) and concentrated under reduced pressure to provide crude2-(trimethylsilyl)benzo[b]thiophene-5-carbaldehyde (762 g) as a buffsolid. ¹H NMR (CDCl₃) δ 10.10 (s, 1H), 8.28 (s, 1H), 7.99 (d, J=8.4 Hz,1H), 7.83 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 0.40-0.38 (m, 9H); LC/MS(ES⁺) m/z 235.1 [M+H]⁺.

(C) A mixture of 2-(trimethylsilyl)benzo[b]thiophene-5-carbaldehyde (956g, 2.9 mol) and TFA (4.5 L) was stirred at 50° C. for 3.5 h. Acetic acid(4.5 L) was then added, and once the temperature again reached 50° C., asolution of Br₂ (718.5 g, 4.50 mol) in acetic acid (4.5 L) was added indrop-wise fashion over a period of 2 h. The reaction was stirred at 50°C. for an additional 2 h, and then was allowed to stir overnight at rt.The reaction mixture was then filtered and the filtrate was poured intoice water (65 L, 5-10° C.), stirred for 2 h, and then filtered. Theprecipitate was washed successively with water, aq. NaHCO₃ solution (5%w/w) and water, and then air-dried (4 d) to afford3-bromobenzo[b]thiophene-5-carbaldehyde (793 g, 83% w/w purity, by ¹HNMR) as a yellow solid. ¹H NMR (CDCl₃) δ 10.16 (s, 1H), 8.32 (s, 1H),7.99-7.93 (m, 2H), 7.57 (s, 1H); LC/MS (ES⁺) m/z 240.9 [M+H]⁺, 242.9[M+H+2]⁺.

(D) A mixture of 3-bromo-1-benzothiophene-5-carbaldehyde (1153 g, 83%w/w purity by ¹H NMR, 3.988 mol), (2-methylphenyl) boronic acid(purchased from Hebei Meixing Chemical Co., Ltd., 1627 g, 40% w/w purityby ¹H NMR, 4.786 mol), DME (9.2 L), H₂O (2.3 L), Na₂CO₃ (1070 g, 10.09mol) and Pd(PPh)₃Cl₂ (140 g, 0.20 mmol), maintained under an inertnitrogen atmosphere, was stirred for 3 h at 80° C., then allowed to coolto rt. After phase separation and removal of the aqueous phase, theorganic phase was diluted with MTBE (5.5 L), washed successively withwater (2×5.5 L) and satd. aq. NaCl (5.5 L), then concentrated underreduced pressure. The resultant crude solid was dissolved in MeCN (5 L)and quantified by ¹H NMR (15.0% w/w purity).

The above solution of crude3-(2-methylphenyl)benzo[b]thiophene-5-carbaldehyde (5334 g, 15.0% w/w by¹H NMR assay, 1.0 eq.) was further diluted with acetonitrile (12 L) andthe resultant solution was heated to 50° C. with stirring. Satd. aq.NaHSO₃ solution (825 g of NaHSO₃ in 2007 g of H₂O) was added indrop-wise fashion over a period of 1.5 h, maintaining a reactiontemperature of 50° C., and the solution was stirred for an additional 2h then cooled to 5 to 10° C. After 1 h, the cooled mixture was filteredand the precipitate was slurried with MeCN (8 L) and filtered. Theprecipitate was stirred in water (10.6 L) for 10 min at rt; Na₂CO₃ (933g) was added and the mixture was stirred at rt for 1.5 h. DCM (10.6 L)was added and the mixture was stirred for 3.5 h. After phase separation,the aqueous layer was extracted with DCM (1×4 L) and the combinedorganic extracts were washed with water (2×4 L) and concentrated underreduced pressure to afford3-(2-methylphenyl)benzo[b]thiophene-5-carbaldehyde as a dark oil (850 g,91% w/w purity by ¹H NMR). ¹H NMR (DMSO-d₆) δ 10.06 (s, 1H), 8.29 (d,J=8.4 Hz, 1H), 7.93-7.88 (m, 3H), 7.44-7.31 (m, 4H), 2.15 (s, 3H); LC/MS(ES⁺) m/z 253.1 [M+H]⁺.

(E) To a cooled (0-5° C.) solution of3-(2-methylphenyl)benzo[b]thiophene-5-carbaldehyde (800 g, 91% w/wpurity, 2.89 mol), toluene (4 L) and methanol (400 mL), maintained underan inert nitrogen atmosphere, was added NaBH₄ (54.6 g, 1.445 mol, 0.50eq.) in portions. After stirring for 1 h, the reaction was quenched bythe drop-wise addition of acetone (110 mL) over 20 min, maintaining areaction temperature below 20° C. 1N aq. HCl (1.5 L) was then added andafter phase separation, the aqueous phase was extracted with toluene(1×4 L). The combined organic phase was washed with aq. NaHCO₃ (5% w/w,4 L) and concentrated under reduced pressure. The residue thus obtainedwas dissolved in EtOH (8 L); Ecosorb C-941 (20% w/w) was added and theresulting suspension was refluxed for 30 min, and then filtered. Thefiltrate was concentrated under reduced pressure to a volume of ˜0.5 L;heptane (4 L) was then added and the resultant solution was stirred at55-60° C. for 1.5 h. The solution was allowed to gradually cool to rt,then was slowly further cooled to 0-5° C. The resultant suspension wasstirred at this temperature for an additional 1 h, and then filtered.The filter cake was collected and dried at 25-30° C. to give 580 g of(3-(2-methylphenyl)benzo[b]thiophen-5-yl)methanol as a white solid(purity: 99.3 LCAP, yield 79%). ¹H NMR (CDCl₃) δ 7.91 (dd, J=8.0, 1.4Hz, 1H), 7.41-7.28 (m, 7H), 4.74 (s, 2H), 2.17 (s, 3H); LC/MS (ES⁺) m/z237.1 [M-OH]⁺.

(F) To a cooled (0-5° C.) solution of SOCl₂ (175.8 g, 1.46 mol, 2.50eq.) and dichloromethane (1.2 L) under an inert nitrogen atmosphere wasadded a solution of (3-(2-methylphenyl)benzo[b]thiophen-5-yl)methanol(150 g, 99.3% purity, 0.586 mol) and TEA (23.66 g, 0.234 mol, 0.40 eq.)in dichloromethane (300 mL) in drop-wise fashion over a period of 45min, and the resultant cooled solution was stirred for an additional 1h. The reaction was then quenched by the addition of ice water (1.5 L).After phase separation, the organic layer was washed with satd. aq. NaCl(1.5 L) and concentrated under reduced pressure to afford crude5-(chloromethyl)-3-(2-methylphenyl)benzo[b]thiophene as a red oil (160g, 97.9% w/w purity by ¹H NMR). ¹H NMR (CDCl₃) δ 7.89 (dd, J=6.0, 2.7Hz, 1H), 7.41-7.37 (m, 2H), 7.35-7.27 (m, 5H), 4.63 (s, 2H), 2.16 (s,3H); LC/MS (ES⁺) m/z 237.1 [M−Cl]⁺.

(G) A mixture of 5-(chloromethyl)-3-(2-methylphenyl)benzo[b]thiophene(435 g, 97.9% purity, 1.56 mol), (3S)-ethyl3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator, Inc.,Research Triangle Park, N.C.; Cat. # PB05708) (380.4 g, 1.61 mol, 1.05eq.) and Cs₂CO₃ (1185 g, 3.56 mol, 2.28 eq.) in MeCN (22 L) was stirredat rt overnight. The mixture was filtered and the filter cake was washedwith MeCN (2 L). The combined filtrates were concentrated under reducedpressure and the resultant residue was purified by silica gelchromatography (2-50% EtOAc/n-heptane) to afford (3S)-ethyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(700 g, 94% w/w purity by ¹H NMR). ¹H NMR (CDCl₃) δ 7.92 (d, J=8.7 Hz,1H), 7.46-7.34 (m, 2H), 7.37-7.24 (m, 7H), 6.88 (dd, J=11.6, 2.9 Hz,2H), 5.08 (s, 2H), 4.16-4.01 (m, 3H), 2.76-2.58 (m, 2H), 2.15 (s, 3H),1.81 (d, J=2.4 Hz, 3H), 1.20 (t, J=7.2 Hz, 3H); LC/MS (ES⁺) m/z 469.1[M+H]⁺.

(H) A mixture of (3S)-ethyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(630 g, 94% purity, 1.25 mol), THF (9.0 L), purified water (1.2 L), MeOH(0.6 L) and anhydrous LiOH (150 g, 6.25 mol) was stirred at rt for 18 hand then concentrated under reduced pressure. The residue thus obtainedwas taken up in purified water (9.5 L) and acidified to pH 2-3 with 6NHCl (1.1 L). The resulting solution was extracted with EtOAc (2×5 L) andthe combined organic extracts were filtered and concentrated underreduced pressure. The residue thus obtained was taken up in HOAc (1 L),and the mixture was concentrated under reduced pressure at 40-45° C.This step was repeated with 400 mL of HOAc. The residue was then takenup in HOAc (2.6 L) and the mixture was heated at 60-65° C. for 3 h,after which time purified water (0.8 L) was added in drop-wise fashionover a period of 3 h. The resulting suspension was stirred at 60-65° C.for 2 h, and then at rt for 14 h. The suspension was filtered and thefilter cake was washed successively with a 50% (v/v) solution ofAcOH/H₂O (2×1.0 L), and purified water (2×0.6 L). The filter cake wasdried under vacuum at 50-55° C. for 12 h to provide 550 g of whitesolid. The solid was dissolved in EtOAc (3.0 L) and after stirring at rtfor 1 h, the solution was filtered and concentrated under reducedpressure. The residue was then treated with n-heptane (9.0 L) and theresultant suspension was stirred at rt for 5 h and filtered. The filtercake was dried under vacuum at 50-55° C. to afford(3S)-3-[4-[[3-(2-methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (515 g, purity 99.3% by HPLC, 97.3% ee) as a white solid. ¹H NMR(DMSO-d₆) δ 12.22 (s, 1H), 8.07 (d, J=6.3 Hz, 1H), 7.71 (s, 1H), 7.48(dd, J=6.2, 1.1 Hz, 1H), 7.40-7.22 (m, 7H), 6.90 (d, J=6.6 Hz, 2H), 5.16(s, 2H), 3.92 (td, J=5.7, 1.8 Hz, 1H), 2.59 (dd, J=11.7, 6 Hz, 2H), 2.08(s, 3H), 1.76 (d, J=1.8 Hz, 3H). ¹³C NMR (DMSO-d₆) δ 172.3, 157.5,139.3, 139.0, 137.0, 136.8, 135.2, 134.1, 133.9, 130.8, 130.6, 128.7,128.5, 126.4, 126.0, 124.8, 123.6, 122.2, 115.3, 81.1, 78.6, 69.7, 43.3,33.1, 20.3, 3.7; LC/MS (ES⁺) m/z 441.1 [M+H]⁺.

Example 3(3S)-3-[4-[[3-[4-[(4-Hydroxy-1,1-dioxothian-4-yl)methoxy]-2-methylphenyl]-benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 3

(A) 5-Hydroxymethyl-3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene wasprepared from 3-bromo-5-hydroxymethylbenzothiophene (from Example 1,Step A) and 4-hydroxy-2-methylphenylboronic acid following GeneralProcedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst. LC/MS:mass calcd. for C₁₆H₁₄O₂S: 270.35, found 293.0 [M+Na]⁺.

(B) A mixture of5-hydroxymethyl-3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene (162 mg;0.6 mmol), 1-oxa-6-thiaspiro[2.5]octane 6,6-dioxide (107 mg; 0.66 mmol)and K₂CO₃ (138 mg; 1 mmol) in DMF (1.5 mL) was stirred at 90° C. for 6h. After cooling to rt, the reaction was partitioned between EtOAc andaq NH₄Cl and the aqueous layer was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with 5-80% EtOAc in heptanes to afford4-hydroxy-4-((4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)methyl)tetrahydro-2H-thiopyran1,1-dioxide (245 mg, 94%). LC/MS: mass calcd. for C₂₂H₂₄O₅S₂: 432.56,found 455.0 [M+Na]⁺.

(C) (3S)-Methyl3-(4-((3-(4-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from4-hydroxy-4-((4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)methyl)tetrahydro-2H-thiopyran1,1-dioxide and (3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared asdescribed in WO 2005086661) following General Procedure B using PPh₃ andDBAD. MS: mass calcd. for C₃₅H₃₆O₇S₂: 632.8, found 633.2 [M]⁺, 655.2[M+Na]⁺.

(D)(3S)-3-[4-[[3-[4-[(4-Hydroxy-1,1-dioxothian-4-yl)methoxy]-2-methylphenyl]-benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 3) was prepared from (3S)-methyl3-(4-((3-(4-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base and 2N HCl for reactionacidification. ¹H NMR (CDCl₃) δ 7.92 (d, J=8.1 Hz, 1H), 7.37-7.49 (m,2H), 7.27-7.32 (m, 3H), 7.22 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.6 Hz, 3H),6.82 (dd, J=8.1, 2.5 Hz, 1H), 5.09 (s, 2H), 3.98-4.10 (m, 1H), 3.93 (s,2H), 3.42-3.59 (m, 2H), 2.92-3.02 (m, 2H), 2.80 (dd, J=15.7, 8.1 Hz,1H), 2.70 (dd, J=15.7, 7.1 Hz, 1H), 2.13 (s, 3H), 1.83 (d, J=2.53 Hz,3H). LC/MS: mass calcd. for C₃₄H₃₄O₇S₂: 618.8, found 619.0 [M]⁺.

Example 4(3S)-3-[4-[[3-[2-Methyl-4-(3-methylsulfonylpropoxy)phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 4

(A) To a solution of 3-methylthiopropanol (1.6 g; 15.07 mmol) and tosylchloride (3.16 g; 16.57 mmol) in DCM (10 mL) was added pyridine (1.46mL; 18.08 mmol) in drop-wise fashion, and the resultant mixture wasstirred at rt for 1 h. The mixture was then concentrated under reducedpressure and the residue thus obtained was purified by silica gelchromatography eluting with 0-50% EtOAc in hexanes to afford3-(methylthio)propyl 4-methylbenzenesulfonate (3.6 g; 92%) as acolorless oil. LC/MS: mass calcd. for C₁₁H₁₆O₃S₂: 260.38, found 283.1[M+Na]⁺.

(B) To an ice-cooled solution of 3-(methylthio)propyl4-methylbenzenesulfonate (3.6 g; 13.8 mmol) in MeOH (70 mL) was added asuspension of monopersulfate compound (17 g; 27.4 mmol) in water (70 mL)in a portion-wise fashion. Upon completion of the addition, the mixturewas allowed to warm to rt, and stirring was continued for 20 h. Thereaction was partially concentrated to remove the MeOH and the mixturewas further diluted with water and extracted with EtOAc (2×). Thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 0-67% EtOAc in hexanes to afford3-(methylsulfonyl)propyl 4-methylbenzene-sulfonate (3.72 g, 92%) as awhite solid. LC/MS: mass calcd. for C₁₁H₁₆O₅S₂: 292.38, found 315.1[M+Na]⁺.

(C) A mixture of5-hydroxymethyl-3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene (fromExample 3) (108 mg; 0.4 mmol), 3-(methylsulfonyl)propyl4-methylbenzenesulfonate (292 mg; 1.0 mmol) and K₂CO₃ (82 mg; 0.6 mmol)in DMF (1.0 mL) was stirred at 90° C. for 6 h. After cooling to rt, thereaction was partitioned between EtOAc and aq NH₄Cl and the aqueouslayer was extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 5-60% EtOAc in heptanes to afford5-hydroxymethyl-3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophene(87 mg, 56%). LC/MS: mass calcd. for C₂₀H₂₀O₄S₂: 390.52, found 413.1[M+Na]⁺.

(D) (3S)-Methyl3-(4-((3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo-[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from5-hydroxymethyl-3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiopheneand (3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared as describedin WO 2005086661) following General Procedure B using PPh₃ and DBAD.LC/MS: mass calcd. for C₃₃H₃₄O₆S₂: 590.76, found 591.0 [M]⁺, 613.0[M+Na]⁺.

(E)(3S)-3-[4-[[3-[2-Methyl-4-(3-methylsulfonylpropoxy)phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 4) was prepared from (3S)-methyl3-(4-((3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base and 2N HCl for reactionacidification. ¹H NMR (CDCl₃) δ 7.92 (d, J=9.1 Hz, 1H), 7.40-7.48 (m,2H), 7.27-7.32 (m, 3H), 7.20 (d, J=8.1 Hz, 1H), 6.83-6.95 (m, 3H), 6.80(dd, J=8.6, 2.5 Hz, 1H), 5.08 (s, 2H), 4.17 (t, J=5.6 Hz, 2H), 3.98-4.09(m, 1H), 3.25-3.35 (m, 2H), 2.98 (s, 3H), 2.79 (dd, J=15.7, 8.1 Hz, 1H),2.69 (dd, J=15.7, 7.1 Hz, 1H), 2.12 (s, 3H), 1.82 (d, J=2.5 Hz, 3H).LC/MS: mass calcd. for C₃₂H₃₂O₆S₂: 576.73, found 577.0 [M]⁺.

Example 5(3S)-3-[4-[[3-[4-(1,1-Dioxo-1,4-thiazinane-4-carbonyl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 5

(A) Methyl 4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylbenzoatewas prepared from 3-bromo-5-hydroxymethylbenzothiophene (from Example1A) and methyl3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoatefollowing General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst. LC/MS: mass calcd. for C₁₈H₁₆O₃S: 312.39, found 335.0 [M+Na]⁺.

(B) 4-(5-(Hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylbenzoic acid wasprepared from methyl4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylbenzoate followingGeneral Procedure C. LC/MS: mass calcd. for C₁₇H₁₄O₃S: 298.36, found321.0 [M+Na]⁺.

(C) To a solution of4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylbenzoic acid (179 mg;0.6 mmol), thiomorpholine 1,1-dioxide (162 mg; 1.2 mmol) and HATU (456mg; 1.2 mmol) in DMF (2 mL) was added DIEA (0.41 mL; 2.4 mmol) and theresultant solution was stirred at rt for 4 h. The mixture was dilutedwith EtOAc and washed sequentially with aq. NH₄Cl and water. The organiclayer was dried (Na₂SO₄), filtered and concentrated under reducedpressure. The resultant residue was partially purified by silica gelchromatography eluting with 30-70% EtOAc in heptanes to afford(1,1-dioxidothiomorpholino)(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)methanone(245 mg, 69%; ˜75% purity), which was used directly in the next step.LC/MS: mass calcd. for C₂₁H₂₁NO₄S₂: 415.53, found 416.1 [M+Na]⁺.

(D) (3S-Methyl3-(4-((3-(4-(1,1-dioxidothiomorpholine-4-carbonyl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(1,1-dioxidothiomorpholino)(4-(5-(hydroxymethyl)benzo[b]-thiophen-3-yl)-3-methylphenyl)methanoneand (3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared as describedin WO 2005086661) following General Procedure B using PPh₃ and DBAD.LC/MS: mass calcd. for C₃₄H₃₃NO₆S₂: 615.77, found 616.2 [M]⁺, 638.2[M+Na]⁺.

(E)(3S)-3-[4-[[3-[4-(1,1-Dioxo-1,4-thiazinane-4-carbonyl)-2-methylphenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 5) was prepared from (3S-methyl3-(4-((3-(4-(1,1-dioxidothiomorpholine-4-carbonyl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base and 2N HCl for reactionacidification. ¹H NMR (CDCl₃) δ 7.94 (d, J=8.6 Hz, 1H), 7.37-7.48 (m,3H), 7.31-7.37 (m, 2H), 7.27-7.31 (m, 3H), 6.87 (d, J=9.1 Hz, 2H), 5.15(s, 2H), 3.92-4.40 (m, 5H), 3.13 (br. s., 4H), 2.83 (dd, J=15.7, 7.1 Hz,1H), 2.70 (dd, J=15.7, 8.1 Hz, 1H), 1.82 (d, 3H). LC/MS: mass calcd. forC₃₃H₃₁NO₆S₂: 601.74, found 602.1 [M]⁺, 625.0 [M+Na]⁺.

Example 6(3S)-3-[4-[[3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 6

(A) 4-(4-Bromo-3-methylphenyl)-3,6-dihydro-2H-thiopyran was preparedfrom 2-bromo-5-iodotoluene and2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefollowing General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst. LC/MS: mass calcd. for C₁₂H₁₃BrS: 269.21, found 269.0 [M]⁺.

(B) To an ice-cooled solution of4-(4-bromo-3-methylphenyl)-3,6-dihydro-2H-thiopyran (1.12 g; 4.16 mmol)in DCM (15 mL) was added a solution of mCPBA (1.865 g; 8.32 mmol) in DCM(15 mL) in drop-wise fashion. After stirring at 0° C. for 0.5 h, thereaction mixture was poured into a mixture of DCM (30 mL) and satd. aq.Na₂CO₃ (60 mL). The aqueous layer was extracted with DCM and thecombined organic extracts were washed with satd. aq. Na₂CO₃, dried(Na₂SO₄), filtered and concentrated under reduced pressure. Theresultant residue was purified by silica gel chromatography eluting with5-40% EtOAc in DCM to afford4-(4-bromo-3-methylphenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (815 mg,65%). MS: mass calcd. for C₁₂H₁₃BrO₂S: 301.20, found 323.0 [M+Na]⁺,325.0 [M+2+Na]⁺.

(C)4-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide was prepared from4-(4-bromo-3-methylphenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and KOAc in place of K₂CO₃.LC/MS: mass calcd. for C₁₈H₂₅BO₄S: 348.27, found 349.2 [M+H]⁺.

(D)4-(4-(5-(Hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide was prepared from4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide and 3-bromo-5-hydroxymethylbenzothiophene (from Example 1A)following General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst. LC/MS: mass calcd. for C₂₁H₂₀O₃S₂: 384.52, found 407.0[M+Na]⁺.

(E) (3S)-Methyl3-(4-((3-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide and (3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared asdescribed in WO 2005086661) following General Procedure B using PPh₃ andDBAD. The product was taken directly onto the following step.

(F)(3S)-3-[4-[[3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 6) was prepared from (3S-methyl3-(4-((3-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base and 2N HCl for reactionacidification. Purification of the product thus obtained was carried outby silica gel chromatography eluting first with 40-100% EtOAc inheptanes, then with 2-4% MeOH in EtOAc. ¹H NMR (CDCl₃) δ 7.93 (d, J=8.1Hz, 1H), 7.41-7.50 (m, 6H), 7.21-7.36 (m, 6H [overlapping with CHCl₃signal]), 6.89 (d, J=8.6 Hz, 2H), 5.96 (t, J=4.3 Hz, 1H), 5.09 (s, 2H),3.97-4.12 (m, 1H), 3.84 (d, J=2.0 Hz, 2H), 3.15-3.37 (m, 4H), 2.80 (dd,J=15.7, 8.1 Hz, 1H), 2.69 (dd, J=15.7, 7.1 Hz, 1H), 2.16 (s, 3H), 1.82(d, J=2.5 Hz, 3H). LC/MS: mass calcd. for C₃₃H₃₀O₅S₂: 570.73, found571.0 [M]⁺, 593.1 [M+Na]⁺, 610.0 [M+K]⁺.

Example 7(3S)-3-[4-[[3-(4-Hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 7

(A) To an ice-cooled solution of 4-bromo-3-methylphenol (43 g; 229.9mmol) in THF (300 mL) was added NaH (13.8 g; 575 mmol) portion-wise.After stirring for 0.5 h, methoxymethyl chloride (22.8 mL; 298.9 mmol)was added in drop-wise fashion to the cooled reaction mixture and afterwarming to rt, the resultant solution was stirred for an additional 2 h.Ether (300 mL) was then added and the mixture was washed with 3M NaOH(2×100 mL), dried (Na₂SO₄), filtered and concentrated under reducedpressure to afford 1-bromo-4-(methoxymethoxy)-2-methylbenzene. ¹H NMR(DMSO-d₆) δ 7.47-7.45 (m, 1H), 7.03 (d, J=2.8 Hz, 1H), 6.83-6.80 (m,1H), 5.18 (s, 2H), 3.34 (s, 3H), 2.38 (s, 3H).

(B)2-(4-(Methoxymethoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared from 1-bromo-4-(methoxymethoxy)-2-methylbenzene andbis(pinacolato)diboron following General Procedure A, using PdCl₂(dppf)CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃, and DMSO assolvent in place of dioxane/water. The isolated product was useddirectly in the subsequent step without further characterization.

(C) (3-(4-(Methoxymethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolwas prepared from2-(4-(methoxymethoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3-bromo-5-hydroxymethylbenzothiophene (from Example 1A) followingGeneral Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst.¹H NMR (DMSO-d₆) δ 7.97-7.95 (m, 1H), 7.57 (s, 1H), 7.34-7.32 (m, 2H),7.18 (d, J=8.4 Hz, 1H), 7.04-7.03 (m, 1H), 6.98-6.95 (m, 1H), 5.241 (s,2H), 4.57-4.55 (m, 2H), 3.43 (s, 3H), 2.09 (s, 3H).

(D) (3S)-Methyl3-(4-((3-(4-hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(3-(4-(methoxymethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanol and(3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared as described in WO2005086661) following General Procedure B using PPh₃ and DBAD. ¹H NMR(DMSO-d₆) δ 8.06 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.49-7.43 (m, 2H),7.25-7.17 (m, 3H), 7.04-7.03 (m, 1H), 6.98-6.91 (m, 3H), 5.25 (s, 4H),3.98-3.94 (m, 1H), 3.57 (s, 3H), 3.42 (s, 3H), 2.69-2.67 (m, 2H), 2.06(s, 3H), 1.77-1.76 (s, 3H).

(E) To a solution of (3S)-methyl3-(4-((3-(4-hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(1.9 g; 3.69 mmol) in MeOH (50 mL) was added conc. HCl (0.05 mL) and theresultant solution was stirred at 62° C. for 1 h. The reaction was thenconcentrated under reduced pressure and the residue was purified bysilica gel chromatography eluting with EtOAc/petroleum ether (1:5) toprovide methyl(3S)-3-(4-[[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]methoxy]phenyl)hex-4-ynoateas a light yellow solid (1.4 g; 80%). ¹H NMR (CDCl₃) δ 9.48 (s, 1H),8.03-8.02 (m, 1H), 7.60 (s, 1H), 7.48-7.47 (m, 2H), 7.44-7.42 (m, 2H),6.93-6.90 (m, 2H), 6.76-6.68 (m, 2H), 5.17 (s, 2H), 3.56 (s, 3H),2.70-2.67 (m, 2H), 2.00-1.99 (m, 3H), 1.77-1.76 (m, 3H). LC/MS: masscalcd. for C₂₉H₂₆O₄S: 470.58, found 469.1 [M−H]⁻.

(F)(3S)-3-[4-[[3-(4-Hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 7) was prepared from (3S)-methyl3-(4-((3-(4-hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using NaOH as base, THF/water as solvent2N HCl for reaction acidification. Following extraction of the crudeproduct, the residue was purified by silica gel chromatography elutingwith 3% MeOH in DCM. ¹H NMR (CDCl₃) δ 7.90 (d, J=9.1 Hz, 1H), 7.39-7.49(m, 2H), 7.27 (m, 3H), 7.13 (d, J=8.1 Hz, 1H), 6.88 (d, J=8.1 Hz, 2H),6.79 (s, 1H), 6.73 (d, J=8.1 Hz, 1H), 5.08 (s, 2H), 4.04 (m, 1H),2.61-2.87 (m, 2H), 2.07 (s, 3H), 1.81 (s, 3H). LC/MS: mass calcd. forC₂₈H₂₄O₄S: 456.56, found 457.2 [M]⁺, 479.2 [M+Na]⁺.

Example 8(3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 8

(A) A mixture of4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide (from Example 6) (192 mg; 0.5 mmol) and 10% Pd/C (80 mg) inEtOH (6 mL) was prepared under an inert N₂ atmosphere and warmed to45-50° C. A solution of ammonium formate (472 mg, 7.5 mmol) in water (1mL) was added and the mixture was stirred for 5 h. After cooling to rt,the mixture was diluted with EtOAc (10 mL), filtered and concentratedunder reduced pressure. The residue was treated with a mixture ofEtOAc/water (2/20 mL), followed by heptanes (30 mL), and the resultingsolid product was filtered and washed successively with water andheptanes to afford pure4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)tetrahydro-2H-thiopyran1,1-dioxide (136 mg, 70%). LC/MS: mass calcd. for C₂₁H₂₂O₃S₂: 386.54,found 409.0 [M+Na]⁺.

(B) (3S)-Methyl3-(4-((3-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)tetrahydro-2H-thiopyran1,1-dioxide and (3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared asdescribed in WO 2005086661) following General Procedure B using PPh₃ andDBAD. LC/MS: mass calcd. for C₃₄H₃₄O₅S₂: 486.77, found 587.3 [M]⁺; 609.2[M+Na]⁺.

(C)(3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)-2-methylphenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 8) was prepared from (3S)-methyl3-(4-((3-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using NaOH as base and 2M citric acid forreaction acidification. ¹H NMR (CDCl₃) δ 7.92 (d, J=8.6 Hz, 1H),7.42-7.48 (m, 2H), 7.22-7.32 (m, 4H), 7.19 (s, 1H), 7.13 (d, J=7.6 Hz,1H), 6.89 (d, J=9.1 Hz, 2H), 5.08 (s, 2H), 4.00-4.08 (m, 1H), 3.14-3.23(m, 4H), 2.74-2.87 (m, 2H), 2.64-2.73 (m, 1H), 2.40-2.57 (m, 2H), 2.29(d, J=14.7 Hz, 2H), 2.14 (s, 3H), 1.82 (d, J=2.5 Hz, 3H). LC/MS: masscalcd. for C₃₃H₃₂O₅S₂: 572.75, found 595.3 [M+Na]⁺.

Example 9(3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)oxy-2-methyl-phenyl]-2-methyl-benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 9

(A) Methyl3-(4-hydroxy-2-methylphenyl)-2-methylbenzo[b]thiophene-5-carboxylate wasprepared from methyl 3-bromo-2-methylbenzo[b]thiophene-5-carboxylate and(4-hydroxy-2-methylphenyl)boronic acid following General Procedure A,using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst. MS: mass calcd. forC₁₈H₁₆O₃S: 312.39, found 313.2 [M+H]⁺, 335.1 [M+Na]⁺.

(B) Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)-2-methylbenzo[b]thiophene-5-carboxylatewas prepared from methyl3-(4-hydroxy-2-methylphenyl)-2-methylbenzo[b]thiophene-5-carboxylate and4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide following General ProcedureB using PPh₃ and DBAD. MS: mass calcd. for C₂₃H₂₄O₅S₂: 444.57, found445.0 [M]⁺, 467.1 [M+Na]⁺.

(C) To an ice-cooled solution of methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)-2-methylbenzo[b]thiophene-5-carboxylate(290 mg; 0.65 mmol) in dry DCM (3 mL) under argon was added DIBAL-H (1Min DCM, 2 mL; 2 mmol). After stirring for 0.5 h, the mixture was pouredinto a vigorously stirring mixture of sodium potassium tartrate (1M inwater, 8 mL) and DCM (5 mL) and stirring was continued for 1 h. The twophases were separated, and the aqueous phase was extracted with DCM (10mL×2). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford4-(4-(5-(hydroxymethyl)-2-methylbenzo[b]thiophen-3-yl)-3-methylphenoxy)tetrahydro-2H-thiopyran1,1-dioxide (265 mg, 98%). LC/MS: mass calcd. for C₂₂H₂₄O₄S₂: 416.56,found 399.1 [M-OH]⁺, 439.0 [M+Na]⁺.

(D)4-(4-(5-(Chloromethyl)-2-methylbenzo[b]thiophen-3-yl)-3-methylphenoxy)-tetrahydro-2H-thiopyran1,1-dioxide was prepared from4-(4-(5-(hydroxymethyl)-2-methylbenzo[b]thiophen-3-yl)-3-methylphenoxy)tetrahydro-2H-thiopyran1,1-dioxide following General Procedure D. ¹H NMR (CDCl₃) δ 7.78 (d,J=8.6 Hz, 1H), 7.29-7.34 (m, 1H), 7.14 (s, 1H), 7.11 (d, J=8.1 Hz, 1H),6.93 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.1, 2.5 Hz, 1H), 4.72 (br. s., 1H),4.61 (s, 2H), 3.42-3.55 (m, 2H), 2.99 (d, J=13.1 Hz, 2H), 2.50-2.60 (m,2H), 2.36-2.48 (m, 2H), 2.34 (s, 3H), 2.04 (s, 3H).

(E) (3S)-Methyl3-(4-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)-2-methylbenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from4-(4-(5-(chloromethyl)-2-methylbenzo[b]thiophen-3-yl)-3-methylphenoxy)-tetrahydro-2H-thiopyran1,1-dioxide and (3S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (prepared asdescribed in WO 2005086661) following General Procedure E. ¹H NMR(CDCl₃) δ 7.80 (d, J=8.6 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.22-7.28 (m,2H), 7.17 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.80-6.93 (m, 4H), 5.02 (s,2H), 4.71 (br. s., 1H), 3.99-4.08 (m, 1H), 3.65 (s, 3H), 3.43-3.54 (m,2H), 2.93-3.03 (m, 2H), 2.70-2.79 (m, 1H), 2.59-2.68 (m, 1H), 2.49-2.59(m, 2H), 2.36-2.47 (m, 2H), 2.34 (s, 3H), 2.02 (s, 3H), 1.82 (d, J=2.5Hz, 3H).

(F)(3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)oxy-2-methyl-phenyl]-2-methyl-benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid (Cpd 9) was prepared from (3S)-methyl3-(4-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)-2-methylbenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using NaOH as base and 2M citric acid forreaction acidification. ¹H NMR (CDCl₃) δ 7.79 (d, J=8.1 Hz, 1H), 7.35(d, J=8.1 Hz, 1H), 7.28 (s, 1H), 7.17 (s, 1H), 7.11 (d, J=8.1 Hz, 1H),6.80-6.93 (m, 5H), 5.02 (s, 2H), 4.71 (br. s., 1H), 3.99-4.08 (m, 1H),3.42-3.55 (m, 2H), 2.93-3.04 (m, 2H), 2.73-2.83 (m, 1H), 2.63-2.73 (m,1H), 2.48-2.59 (m, 2H), 2.35-2.46 (m, 2H), 2.34 (s, 3H), 2.02 (s, 3H),1.82 (d, J=2.53 Hz, 3H). LC/MS: mass calcd. for C₃₄H₃₄O₆S₂: 602.77,found 603.1 [M]⁺, 625.2 [M+Na]⁺.

Example 10(3S)-3-[4-[[3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 10

(A) 5-Hydroxymethyl-3-(2,6-dimethylphenyl)benzo[b]thiophene was preparedfrom 3-bromo-5-hydroxymethylbenzothiophene (from Example 1A) and2,6-dimethylphenylboronic acid following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₇H₁₆OS: 268.37, found 251.0 [M-17]⁺.

(B) 5-Chloromethyl-3-(2,6-dimethylphenyl)benzo[b]thiophene was preparedfrom 5-hydroxymethyl-3-(2,6-dimethylphenyl)benzo[b]thiophene followingGeneral Procedure D.

(C) (3S)-Methyl3-(4-((3-(2,6-dimethylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from5-chloromethyl-3-(2,6-dimethylphenyl)benzo[b]-thiophene and (3S)-methyl3-(4-hydroxyphenyl)hex-4-ynoate (prepared as described in WO 2005086661)following General Procedure E using DMF as solvent and stirring overnight at 40° C. LC/MS: mass calcd. for C₃₀H₂₈O₃S: 468.61, found 469.0[M]⁺.

(D)(3S)-3-(4-((3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 10) was prepared from (3S)-methyl3-(4-((3-(2,6-dimethylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base and 1N HCl forreaction acidification. ¹H NMR (DMSO-d₆) δ 8.08 (d, J=8.3 Hz, 1H), 7.63(s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.12-7.36 (m, 6H), 6.87 (d, J=8.5 Hz,2H), 5.14 (s, 2H), 3.85-4.03 (m, 1H), 2.31-2.44 (m, 2H), 1.93 (s, 6H),1.76 (d, J=2.3 Hz, 3H) LC/MS: mass calcd. for C₂₉H₂₆O₃S: 454.58, found453.1 [M−H]⁻.

Example 11(3S)-3-(4-((3-(4-(2-(1-Hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 11

(A) To a solution of benzyl 3-hydroxypropanoate (3.35 g, 18.59 mmol),and dihydropyran (3.12 g, 37.09 mmol) in DCM (100 mL) was added PPTS(5.6 g, 22.28 mmol) portion-wise and the resulting solution was stirredovernight at rt. Water (50 mL) was added and after mixing, the phaseswere separated and the aqueous layer was further extracted with DCM(2×50 mL). The combined organic layers were concentrated under reducedpressure and the residue obtained was purified by silica gelchromatography (0-5% EtOAc/petroleum ether) to provide benzyl3-(tetrahydro-2H-pyran-2-yloxy)propanoate as colorless oil (4.1 g, 83.0%yield). LC/MS: mass calcd. for C₁₅H₂₀O₄: 264.32, found: 265.1 [M+H]⁺.

(B) To a solution of benzyl 3-(oxan-2-yloxy)propanoate (4.1 g, 15.51mmol) and THF (60 mL) was added Ti(O-iPr)₄ (2.4 mL, 8.0 mmol) and theresultant mixture was stirred for 30 min. EtMgBr (13.3 mL, 3M, 4 mmol)was then added in drop-wise fashion and the resulting solution wasstirred at rt for 3 h. The reaction was then quenched by the addition ofsatd. aq. NH₄Cl (100 mL) and the mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were concentrated underreduced pressure and the residue thus obtained was purified by silicagel chromatography (0-10% EtOAc/petroleum ether) to obtain1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-cyclopropanol as a colorlessoil (2.1 g, 65.0% yield). LC/MS: mass calcd. for C₁₀H₁₈O₃: 186.25,found: 187.1 [M+H]⁺.

(C) A solution of 1-[2-(oxan-2-yloxy)ethyl]cyclopropan-1-ol (800 mg,4.30 mmol) and PPTS (110 mg, 0.44 mmol) in methanol (40 mL) was stirredovernight at 40° C. The resulting mixture was then concentrated underreduced pressure and the resultant residue was purified by silica gelchromatography (10-50% EtOAc/petroleum ether) to afford1-(2-hydroxyethyl)cyclopropanol as colorless oil (374 mg, 85.3% yield).LC/MS: mass calcd. for C₅H₁₀O₂: 102.13, found: 102.2 [M]⁺.

(D) 3-Bromo-5-(chloromethyl)benzo[b]-thiophene was prepared from3-bromo-5-hydroxymethylbenzothiophene (from Example 1A) followingGeneral Procedure D.

(E) A mixture of 3-bromo-5-(chloromethyl)-1-benzothiophene (200 mg, 0.76mmol), (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (180 mg, 0.77 mmol)(available from Synnovator, Inc., Research Triangle Park, N.C.; Cat. #PB05708) and K₂CO₃ (420 mg, 1.29 mmol) in MeCN (20 mL) was stirredovernight at 50° C. The reaction was then quenched by the addition ofsatd. aq. NH₄Cl (40 mL) and the resulting solution was extracted withethyl acetate (3×40 mL) and the combined organic extracts wereconcentrated under reduced pressure. The resultant residue was purifiedby silica gel chromatography (0-20% EtOAC/petroleum ether) to provide(3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate as acolorless oil (300 mg, 86% yield). LC/MS: mass calcd. for C₂₃H₂₁BrO₃S:457.38, found: 459.0 [M+H]⁺.

(F) (3S)-Ethyl3-(4-((3-(4-hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate and4-hydroxy-2-methylphenylboronic acid following General Procedure A usingPdCl₂(dppf). CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₃₀H₂₈O₄S: 484.61, found: 485.2 [M+H]⁺.

(G) (3S)-Ethyl3-(4-((3-(4-(2-(1-hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-(4-hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)-phenyl)hex-4-ynoateand 1-(2-hydroxyethyl)cyclopropan-1-ol following General Procedure Busing PPh₃ and ADDP. LC/MS: mass calcd. for C₃₅H₃₆O₅S: 568.72 found:569.2 [M⁺].

(H)(3S)-3-(4-((3-(4-(2-(1-Hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 11) was prepared from (3S)-ethyl3-(4-((3-(4-(2-(1-hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. Product purification wasaccomplished by preparative HPLC on a preparative C18, 5μ column (19×100mm) using an acetonitrile/water (0.5% TFA) gradient (50-75%). ¹H NMR(DMSO-d₆) δ 8.06 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.47 (d, J=8.4 Hz,1H), 7.41 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.1 Hz, 1H),6.86-6.93 (m, 4H), 5.17 (s, 2H), 4.21 (t, J=6.9 Hz, 2H), 3.91-3.93 (m,1H), 2.57-2.58 (m, 2H), 2.06 (s, 3H), 1.95 (t, J=6.9 Hz, 2H), 1.76 (s,3H), 0.58-0.62 (m, 2H), 0.46-0.50 (m, 2H). LC/MS: mass calcd. forC₃₃H₃₂O₅S: 540.67, found: 539.2 [M−H]⁻.

Example 12(3S)-3-(4-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 12

(A) (3S)-Ethyl3-(4-((3-(4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from3-(4-((3-(4-hydroxy-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(from Example 11F) and 3-methylbutane-1,3-diol following GeneralProcedure B using PPh₃ and ADDP. LC/MS: mass calcd. for C₃₅H₃₈O₅S:570.74, found: 571.2 [M+H]⁺.

(B)(3S)-3-(4-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 12) was prepared from (3S)-ethyl3-(4-((3-(4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (CD₃OD) δ 7.96 (m, 1H),7.48 (m, 1H), 7.38 (s, 2H), 7.22-7.28 (m, 2H), 7.13-7.16 (m, 1H),6.81-6.95 (m, 4H), 5.16 (s, 2H), 4.19-4.22 (m, 2H), 3.39-4.01 (m, 1H),2.62-2.67 (m, 2H), 2.01-2.08 (m, 5H), 1.82 (s, 3H), 1.38 (s, 6H). LC/MS:mass calcd. for C₃₃H₃₄O₅S: 542.69, found: 543.2 [M+H]⁺.

Example 13(3S)-3-(4-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 13

(A) 4-((4-Bromo-3-methylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane wasprepared from 4-bromo-3-methylphenol and(2,2-dimethyl-1,3-dioxolan-4-yl)methanol following General Procedure Busing PPh₃ and ADDP in toluene (in place of THF) at 60° C.

¹H NMR (CDCl₃) δ 7.38 (d, J=8.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 6.62(dd, J=3.2, 8.8 Hz, 1H), 4.42-4.48 (m, 1H), 4.13-4.17 (m, 1H), 3.99-4.02(m, 1H), 3.86-3.91 (m, 2H), 2.35 (s, 3H), 1.48 (s, 3H), 1.40 (s, 3H).

(B)2-(4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared from4-((4-bromo-3-methylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃ and a reaction temperature of 85° C. overnight. ¹H NMR (CDCl₃) δ7.70 (d, J=8.0 Hz, 1H), 6.69-6.72 (m, 2H), 4.45-4.48 (m, 1H), 4.14-4.18(m, 1H), 4.05-4.08 (m, 1H), 3.87-3.96 (m, 2H), 2.51 (s, 3H), 1.46 (s,3H), 1.40 (s, 3H), 1.32 (s, 12H).

(C) To a solution of 5-bromo-1-benzothiophene (12 g, 56.31 mmol) in dryTHF (300 mL) under an inert atmosphere was added isopropyl magnesiumchloride-lithium chloride complex (1.3 M in THF; 150 mL, 195 mmol) indrop-wise fashion, and the resultant solution was stirred at rt,overnight. DMF (30 mL) was then added in drop-wise fashion and theresultant solution was stirred at rt for 30 min. Water (500 mL) wasadded and the resulting solution was extracted with ethyl acetate (3×500mL). The combined organic extracts were concentrated under reducedpressure and the resultant residue was purified by silica gelchromatography (0-2% EtOAC/petroleum ether) to providebenzo[b]thiophene-5-carbaldehyde (6.9 g, 68%) as a yellow solid. ¹H NMR(DMSO-d₆) δ 10.12 (s, 1H), 8.32 (s, 1H), 8.01 (d, J=8.4 Hz, 1H),7.86-7.89 (m, 1H), 7.57-7.61 (m, 1H), 7.47-7.50 (m, 1H).

(D) To a cooled (15° C.) solution of benzo[b]thiophene-5-carbaldehyde(6.9 g, 52.54 mmol) in HOAc (80 mL) was added a solution of bromine(10.5 g, 65.7 mmol) in HOAc (20 mL) in drop-wise fashion. After stirringat 15° C. for 2 h, water (500 mL) was added, whereupon the solid productprecipitated from the mixture. The precipitate was collected byfiltration and dried under vacuum to provide3-bromobenzo[b]thiophene-5-carbaldehyde (7.8 g, 38% yield) as a yellowsolid. ¹H NMR (CDCl₃) δ 10.17 (s, 1H), 8.32 (s, 1H), 7.93-7.98 (m, 2H),7.78 (s, 1H).

(E)3-(4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophene-5-carbaldehydewas prepared from2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3-bromobenzo[b]thiophene-5-carbaldehyde following General ProcedureA, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ inplace of K₂CO₃. ¹H NMR: (CDCl₃) δ 10.02 (s, 1H), 8.02-8.04 (m, 1H),7.89-7.90 (m, 2H), 7.37 (s, 1H), 7.20-7.26 (m, 1H), 6.82-7.00 (m, 2H),4.50-4.53 (m, 1H), 4.14-4.24 (m, 2H), 3.93-4.08 (m, 2H), 2.15 (s, 3H),1.48-1.50 (m, 3H), 1.42-1.43 (m, 3H).

(F)(3-(4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolwas prepared from3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophene-5-carbaldehydefollowing General Procedure F. LC/MS: mass calcd. for C₂₂H₂₄O₄S: 384.49,found: 367.1 [M-OH]⁺.

(G)4-((4-(5-(Chloromethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolanewas prepared from(3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolfollowing General Procedure D.

(H) (3S)-Ethyl3-(4-((3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from4-((4-(5-(chloromethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolaneand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure E. LC/MS: mass calcd. for C₃₆H₃₈O₆S: 598.75,found: 599.2 [M+H]⁺.

(I) A solution of (3S)-ethyl3-(4-((3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(200 mg, 0.33 mmol) in THF (4 mL) was treated with 2N HCl (4 mL) and theresulting solution was stirred at 60° C. for 30 min. Water (10 mL) wasthen added and the mixture was extracted with EtOAc (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the resultant residue by silica gelchromatography (0-50% EtOAc/petroleum ether) afforded (3S)-ethyl3-(4-((3-(4-(2,3-dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(140 mg, 75% yield) as a colorless oil. LC/MS: mass calcd. forC₃₃H₃₄O₆S: 558.68, found: 559.2 [M±H]⁺.

(J)(3S)-3-(4-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 13) was prepared from (3S)-ethyl3-(4-((3-(4-(2,3-dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d6) δ 8.06 (d, J=8.4Hz, 1H), 7.65 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.23-7.25(m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.86-6.95 (m, 4H), 5.17 (s, 2H),4.98-5.02 (m, 1H), 4.06-4.07 (m, 1H), 4.03-4.07 (m, 1H), 3.82-3.93 (m,3H), 3.46-3.47 (m, 2H), 2.63-2.67 (m, 2H), 2.06 (s, 3H), 1.76 (s, 3H).LC/MS: mass calcd. for C₃₁H₃₀O₆S: 530.63, found: 529.2[M−H]⁻.

Example 14(3S)-3-(4-((3-(2-Methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 14

(A) 3-((4-Bromo-3-methylphenoxy)methyl)-3-methyloxetane was preparedfrom 4-bromo-3-methylphenol and (3-methyloxetan-3-yl)methanol followingGeneral Procedure B using PPh₃ and DBAD at a reaction temperature of 50°C. overnight. LC/MS: mass calcd. for C₁₂H₁₅BrO₂: 271.15, found: 271.0[M]⁺.

(B)4,4,5,5-Tetramethyl-2-(2-methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)-1,3,2-dioxaborolanewas prepared from 3-(4-bromo-3-methylphenoxymethyl)-3-methyloxetane andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ andDMSO as solvent in place of dioxane/water. LC/MS: mass calcd. forC₁₈H₂₇BO₄: 318.22, found: 319.2 [M+H]⁺.

(C) (3S)-Ethyl3-(4-((3-(2-methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from4,4,5,5-tetramethyl-2-(2-methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)-1,3,2-dioxaborolaneand (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) following General Procedure A using PdCl₂(dppf).CH₂Cl₂ asthe palladium catalyst and Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd.for C₃₅H₃₆O₅S: 568.72, found: 569.2 [M]⁺.

(D)(3S)-3-(4-((3-(2-Methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 14) was prepared from (3S)-ethyl3-(4-((3-(2-methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. Product purification wasaccomplished by preparative HPLC on a preparative C18, 5μ column (19×100mm) using an acetonitrile/water (0.5% TFA) gradient (65-95%). ¹H NMR(CD₃OD) δ 7.96 (d, J=8.0 Hz, 1H), 7.47 (d, J=6.8 Hz, 1H), 7.40-7.42 (m,2H), 7.28 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 6.99 (s, 1H),6.90-6.94 (m, 3H), 5.16 (s, 2H), 4.73 (d, J=5.6 Hz, 2H), 4.50 (d, J=6.0Hz, 2H), 4.12 (s, 2H), 3.95-4.05 (m, 1H), 2.57-2.61 (m, 2H), 2.01 (s,3H), 1.81 (s, 3H), 1.49 (s, 3H). LC/MS: mass calcd. for C₃₃H₃₂O₅S:540.67, found: 539.2 [M−H]⁻.

Example 15 (3S)-3-(4-((3-(2-Methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid, Cpd 15

(A) 4-(4-Bromo-3-methylphenoxy)-tetrahydro-2H-pyran was prepared from4-bromo-3-methylphenol and oxan-4-ol following General Procedure B usingPPh₃ and DBAD at a reaction temperature of 50° C. overnight. ¹H NMR(CDCl₃) δ 7.41 (d, J=8.6 Hz, 1H), 6.81 (d, J=3.0 Hz, 1H), 6.62 (dd,J=8.7, 3.0 Hz, 1H), 4.39-4.47 (m, 1H), 3.93-4.00 (m, 2H), 3.53-3.60 (m,2H), 2.35 (s, 3H), 1.95-2.03 (m, 2H), 1.70-1.82 (m, 2H); LC/MS: Calcd.for C₁₂H₁₅BrO₂: 271.2, found: 271.0 [M]⁺, 273.0 [M+2]⁺.

(B)4,4,5,5-Tetramethyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,3,2-dioxaborolanewas prepared from 4-(4-bromo-3-methylphenoxy)-tetrahydro-2H-pyran andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ anda reaction temperature of 70° C. overnight. LC/MS: mass calcd. forC₁₈H₂₇BO₄: 318.2, found: 319.2 [M]⁺.

(C)3-(2-Methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophene-5-carbaldehydewas prepared from 3-bromobenzo[b]thiophene-5-carbaldehyde (from Example13D) and4,4,5,5-tetramethyl-2-[2-methyl-4-(oxan-4-yloxy)phenyl]-1,3,2-dioxaborolanefollowing General Procedure A using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst and Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₂₁H₂₀O₃S:352.45, found: 353.1 [M+H]⁺.

(D)(3-(2-Methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methanolwas prepared from3-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophene-5-carbaldehydefollowing General Procedure F. LC/MS: mass calcd. for C₂₁H₂₂O₃S: 354.46,found: 355.1 [M+H]⁺.

(E)4-(4-(5-(Chloromethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)-tetrahydro-2H-pyranwas prepared from(3-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methanolfollowing General Procedure D.

(F) (3S)-Ethyl3-(4-((3-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from4-(4-(5-(chloromethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)-tetrahydro-2H-pyranand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure E using DMF as solvent at a reactiontemperature of 60° C. for 1 h. LC/MS: mass calcd. for C₃₅H₃₆O₅S: 568.72,found: 569.2 [M]⁺.

(G)(3S)-3-(4-((3-(2-Methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 15) was prepared from (3S)ethyl3-(4-((3-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.35 (br. s, 1H), 8.00-8.04 (m, 1H),7.65 (s, 1H), 7.42-7.49 (m, 2H), 7.23-7.26 (m, 2H), 7.14-7.17 (m, 1H),6.98-6.99 (m, 1H), 6.90-6.93 (m, 3H), 5.17 (s, 2H), 4.60-4.66 (m, 1H),3.84-3.95 (m, 3H), 3.47-3.55 (m, 2H), 2.56-2.59 (m, 2H), 1.99-2.05 (m,5H), 1.76 (s, 3H), 1.56-1.68 (m, 2H). LC/MS: mass calcd. for C₃₃H₃₂O₅S:540.67, found: 541.2 [M+H]⁺.

Example 16(3S)-3-(4-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 16

(A) A mixture of 4-bromo-3-methylphenol (5 g, 26.7 mmol),1-bromo-2-methoxyethane (4.4 g, 31.7 mmol) and K₂CO₃ (15 g, 108.5 mmol)in MeCN (100 mL) was stirred overnight at 80° C. After cooling to rt,the reaction was filtered and the filtrate was concentrated underreduced pressure to afford 1-bromo-4-(2-methoxyethoxy)-2-methylbenzeneas a yellow oil. ¹H NMR (CDCl₃) δ 7.38 (d, J=8.8 Hz, 1H), 6.81 (d, J=2.8Hz, 1H), 6.63 (dd, J=8.4, 2.8 Hz, 1H), 4.06 (t, J=4.8 Hz, 2H), 3.72 (t,J=4.8 Hz, 2H), 3.43 (s, 3H), 2.34 (s, 3H).

(B)2-(4-(2-Methoxyethoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared from 1-bromo-4-(2-methoxyethoxy)-2-methylbenzene andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₆H₂₅BO₄: 292.18, found: 293.2 [M+H]⁺.

(C)3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophene-5-carbaldehydewas prepared from2-(4-(2-methoxyethoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 3-bromobenzo[b]thiophene-5-carbaldehyde (from Example 13D) followingGeneral Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalystand Cs₂CO₃ in place of K₂CO₃. ¹H NMR (CDCl₃) δ 10.02 (s, 1H), 8.02-8.04(m, 1H), 7.88-7.90 (m, 2H), 7.37 (s, 1H), 7.20-7.26 (m, 1H), 6.83-6.94(m, 2H), 4.19-4.21 (m, 2H), 3.37-3.82 (m, 2H), 3.49 (s, 3H), 2.14 (s,3H).

(D)(3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolwas prepared3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophene-5-carbaldehydefollowing General Procedure F. LC/MS: mass calcd. for C₁₉H₂₀O₃S: 328.43,found: 311.0 [M−OH]⁺.

(E)5-(Chloromethyl)-3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophenewas prepared from(3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolfollowing General Procedure D. LC/MS: mass calcd. for C₁₉H₁₉ClO₂S:346.87, found: 347.1 [M]⁺.

(F) (3S)-Ethyl3-(4-((3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from5-(chloromethyl)-3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiopheneand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure E. LC/MS: mass calcd. for C₃₃H₃₄O₅S: 542.69,found: 543.2 [M+H]⁺.

(G)(3S)-3-(4-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 16) was prepared from (3S)-ethyl3-(4-((3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.06 (d, J=8.4Hz, 1H), 7.65 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.23-7.25(m, 2H), 7.16 (d, J=8.0 Hz, 1H), 6.86-6.96 (m, 4H), 5.17 (s, 2H),4.13-4.16 (m, 2H), 3.90-3.95 (m, 1H), 3.68-3.70 (m, 2H), 3.33 (s, 3H),2.54-2.58 (m, 2H), 2.05 (s, 3H), 1.76 (s, 3H). LC/MS: mass calcd. forC₃₁H₃₀O₅S: 514.63, found: 515.2 [M+H]⁺.

Example 17(3S)-3-{4-[(3-{4-[(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoic acid, Cpd 17

(A) To a solution of 4-(hydroxymethyl)tetrahydro-2H-thiane-1,1-dione(2.84 g, 17.29 mmol), 4-dimethylaminopyridine (633 mg, 5.18 mmol) andpyridine (4.10 g, 51.83 mmol) in CHCl₃ (20 mL) was added4-methylbenzene-1-sulfonyl chloride (6.61 g, 34.67 mmol) in portions andthe resulting mixture was stirred at rt for 2 d. Water (30 mL) was thenadded and the mixture was then extracted with CHCl₃ (3×30 mL). Thecombined organic extracts were washed with water (2×50 mL) and thenconcentrated under reduced pressure. Purification of the resultantresidue by silica gel chromatography (0-10% EtOAc/petroleum ether)afforded (1,1-dioxotetrahydro-2H-thian-4-yl)methyl4-methylbenzene-1-sulfonate (5.3 g, 96%) as a white solid. LC/MS: masscalcd. for C₁₃H₁₈O₅S₂: 318.41, found: 319.1 [M+H]⁺.

(B) A mixture of ethyl(3S)-3-(4-[[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]methoxy]phenyl)hex-4-ynoate(70 mg, 0.14 mmol) (from Example 11F),(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)methyl4-methylbenzene-1-sulfonate (55 mg, 0.17 mmol) and Cs₂CO₃ (94 mg, 0.29mmol) in MeCN (5 mL) was stirred overnight at 50° C. Water (20 mL) wasthen added, the mixture was extracted with EtOAc (3×15 mL) and thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the resultant residue by silica gelchromatography (0-25% EtOAc/petroleum ether) afforded ethyl(3S)-3-{4-[(3-{4-[(1,1-dioxotetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoate(63 mg, 69.1% yield) as a colorless oil. LC/MS: mass calcd. forC₃₆H₃₈O₆S₂: 630.81, found: 631.2 [M]⁺.

(C)(3S)-3-{4-[(3-{4-[(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoicacid (Cpd 17) was prepared from ethyl(3S)-3-{4-[(3-{4-[(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 2N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.06 (d, J=8.4Hz, 1H), 7.63 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.24 (d,J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 1H), 6.88-7.00 (m, 4H), 5.16 (s, 2H),3.93-3.95 (m, 3H), 3.18-3.24 (m, 2H), 3.08-3.11 (m, 2H), 2.57-2.59 (m,2H), 2.12-2.19 (m, 3H), 2.05 (s, 3H), 1.76-1.84 (m, 5H). LC/MS: masscalcd. for C₃₄H₃₄O₆S₂: 602.76, found: 603.2 [M]⁺.

Example 18(3S)-3-{4-[(3-{2-Methyl-4-[(3-methyl-1,1-dioxo-thietane-3-yl)methoxy]phenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoicacid, Cpd 18

(A) To an ice-cooled solution of 4-bromo-3-methylphenol (300 mg, 1.60mmol), (3-methylthietan-3-yl)methanol (300 mg, 2.54 mmol) and (n-Bu)₃P(810 mg, 4.02 mmol) in toluene (10 mL) was added ADDP (1020 mg, 4.07mmol). Upon completion of addition, the reaction mixture was warmed to60° C. and stirred for 2 h. The reaction was treated with satd. aq.NH₄Cl (50 mL), extracted with EtOAc (2×50 mL) and the combined organicextracts were concentrated under reduced pressure. Purification of theresultant residue by silica gel chromatography (0-2% EtOAc/petroleumether) afforded 3-((4-bromo-3-methylphenoxy)methyl)-3-methylthietane(0.67 g, crude) as a white solid. ¹H NMR (CDCl₃) δ 7.36-7.42 (m, 1H),6.84-6.85 (m, 1H), 6.63-6.67 (m, 1H), 3.90 (s, 2H), 3.18 (d, J=6.3 Hz,2H), 2.95 (d, J=6.3 Hz, 2H), 2.37 (s, 3H), 1.46 (s, 3H).

(B) To a solution of3-((4-bromo-3-methylphenoxy)methyl)-3-methylthietane (570 mg, 1.37 mmol)and Na₂WO₄.2H₂O (110 mg, 0.35 mmol) in MeOH (50 mL) was added 30% H₂O₂(1.92 g, 16.94 mmol) in drop-wise fashion, and the resulting mixture wasstirred at rt for 2 h. The mixture was then concentrated under reducedpressure and purified directly by silica gel chromatography (0-10%EtOAc/petroleum ether) to afford3-(4-bromo-3-methylphenoxymethyl)-3-methylthietane-1,1-dioxide (412 mg,94% yield) as a colorless oil. ¹H NMR (CDCl₃) δ 7.41-7.44 (m, 1H),6.82-6.83 (m, 1H), 6.61-6.65 (m, 1H), 4.20-4.25 (m, 2H), 3.97 (s, 2H),3.83-3.88 (m, 2H), 2.37 (s, 3H), 1.60 (s, 3H).

(C)3-Methyl-3-[3-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxymethyl]-thietane-1,1-dioxidewas prepared from3-(4-bromo-3-methylphenoxymethyl)-3-methyl-thietane-1,1-dioxide andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, dioxane as solvent andCs₂CO₃ in place of K₂CO₃ at a reaction temperature of 80° C. overnight.¹H NMR (CDCl₃) δ 7.44-7.46 (m, 1H), 6.85-6.86 (m, 1H), 6.64-6.67 (m,1H), 4.23-4.29 (m, 2H), 3.99 (s, 2H), 3.85-3.90 (m, 2H), 2.37 (s, 3H),1.63 (s, 3H), 1.35 (s, 12H).

(D)3-{2-Methyl-4-[(3-methyl-1,1-dioxo-thietan-3-yl)methoxy]phenyl}-1-benzothiophene-5-carbaldehydewas prepared from3-methyl-3-[3-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxymethyl]-thietane-1,1-dioxideand 3-bromobenzo[b]thiophene-5-carbaldehyde (from Example 13D) followingGeneral Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalystand Cs₂CO₃ in place of K₂CO₃ at a reaction temperature of 80° C.overnight. ¹H NMR (CDCl₃) δ 7.44-7.46 (m, 1H), 6.85-6.86 (m, 1H),6.64-6.67 (m, 1H), 4.23-4.29 (m, 2H), 3.99 (s, 2H), 3.85-3.90 (m, 2H),2.37 (s, 3H), 1.63 (s, 3H), 1.35 (s, 12H).

(E)3-{4-[5-(Hydroxymethyl)-1-benzothiophen-3-yl]-3-methylphenoxymethyl}-3-methyl-thietane-1,1-dionewas prepared from3-{2-methyl-4-[(3-methyl-1,1-dioxo-thietan-3-yl)methoxy]phenyl}-1-benzothiophene-5-carbaldehydefollowing General Procedure F. LC/MS: mass calcd. for C₂₁H₂₂O₄S₂:402.53, found: 403.1 [M+H]⁺.

(F)3-{4-[5-(Chloromethyl)-1-benzothiophen-3-yl]-3-methylphenoxymethyl}-3-methyl-thietane-1,1-dionewas prepared from3-{4-[5-(hydroxymethyl)-1-benzothiophen-3-yl]-3-methylphenoxymethyl}-3-methyl-thietane-1,1-dionefollowing General Procedure D. LC/MS: mass calcd. for C₂₁H₂₁ClO₃S₂:420.97; found: 421.1 [M]⁺.

(G) Ethyl(3S)-3-{4-[(3-{2-methyl-4-[(3-methyl-1,1-dioxo-thietan-3-yl)methoxy]phenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoatewas prepared from3-{4-[5-(chloromethyl)-1-benzothiophen-3-yl]-3-methylphenoxymethyl}-3-methyl-thietane-1,1-dioneand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure E at a reaction temperature of 60° C. for 4h. LC/MS: mass calcd. for C₃₅H₃₆O₆S₂: 616.79, found: 617.2 [M]⁺.

(H)(3S)-3-{4-[(3-{2-Methyl-4-[(3-methyl-1,1-dioxo-thietane-3-yl)methoxy]phenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoicacid (Cpd 18) was prepared from ethyl(3S)-3-{4-[(3-{2-methyl-4-[(3-methyl-1,1-dioxo-thietan-3-yl)methoxy]phenyl}-1-benzothiophen-5-yl)methoxy]phenyl}hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. Product purification wasaccomplished by preparative HPLC on a preparative C18, 5μ column (19×100mm) using an acetonitrile/water (0.5% TFA) gradient (65-73%). ¹H NMR(DMSO-d₆+D₂O) δ 8.06 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.47 (d, J=8.4 Hz,1H), 7.40 (s, 1H), 7.18-7.26 (m, 3H), 7.00-7.01 (m, 1H), 6.91-6.95 (m,3H), 5.17 (s, 2H), 4.21-4.26 (m, 2H), 4.11 (s, 2H), 3.90-4.02 (m, 3H),2.57-2.60 (m, 2H), 2.06 (s, 3H), 1.76 (s, 3H), 1.52 (s, 3H). LC/MS: masscalcd. for C₃₃H₃₂O₆S₂: 588.73, found: 589.2 [M]⁺.

Example 19(3S)-3-(4-((3-(2-Chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 19

(A) (3S)-Ethyl3-(4-((3-(2-chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and 2-chlorophenylboronic acid following General ProcedureA, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ inplace of K₂CO₃ at a reaction temperature of 90° C. overnight. LC/MS:mass calcd. for C₂₉H₂₅ClO₃S: 489.02, found: 489.1 [M]⁺.

(B)(3S)-3-(4-((3-(2-Chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 19) was prepared from (3S)-ethyl3-(4-((3-(2-chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. Product purification wasaccomplished by preparative HPLC on a preparative C18, 5μ column (19×100mm) using an acetonitrile/water (0.5% TFA) gradient (40-95%). ¹H NMR(DMSO-d₆) δ 8.09 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.64-7.66 (m, 1H),7.47-7.53 (m, 5H), 7.24 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 5.17(s, 2H), 3.90-3.93 (m, 1H), 2.57 (d, J=7.6 Hz, 2H), 1.76 (s, 3H). LC/MS:mass calcd. for C₂₇H₂₁ClO₃S: 460.97, found: 459.1 [M−H]⁻, 461.1[M−H+2]⁻.

Example 20(3S)-3-(4-((3-(2-Bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 20

(A) 3-(2-Bromophenyl)benzo[b]thiophene-5-carbaldehyde was prepared from3-bromobenzo[b]thiophene-5-carbaldehyde (from Example 13D) and2-bromophenylboronic acid following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₅H₉BrOS: 317.20, found: 317.0 [M]⁺,319.0 [M+2]⁺.

(B) (3-(2-Bromophenyl)benzo[b]thiophen-5-yl)methanol was prepared from3-(2-bromophenyl)benzo[b]thiophene-5-carbaldehyde following GeneralProcedure F. LC/MS: mass calcd. for C₁₅H₁₁BrOS: 319.22, found: 319.0[M]⁺, 321.0 [M+2]⁺.

(C) 3-(2-Bromophenyl)-5-(chloromethyl)benzo[b]thiophene was preparedfrom (3-(2-bromophenyl)benzo[b]thiophen-5-yl)methanol following GeneralProcedure D.

(D) (3S)-Ethyl3-(4-((3-(2-bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from 3-(2-bromophenyl)-5-(chloromethyl)benzo[b]thiopheneand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure E at a reaction temperature of 50° C. for 2h. LC/MS: mass calcd. for C₂₉H₂₅BrO₃S: 533.48, found: 533.1 [M]⁺, 535.1[M+H]⁺.

(E)(3S)-3-(4-((3-(2-Bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 20) was prepared from (3S)-ethyl3-(4-((3-(2-bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 2N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.08 (d, J=8.1Hz, 1H), 7.80-7.85 (m, 2H), 7.40-7.56 (m, 5H), 7.24 (d, J=8.7 Hz, 2H),6.92 (d, J=8.4 Hz, 2H), 5.16 (s, 2H), 3.89-3.94 (m, 1H), 2.58 (d, J=7.5Hz, 2H), 1.77 (s, 3H). LC/MS: mass calcd. for C₂₇H₂₁BrO₃S: 505.42,found: 505.0 [M]⁻, 507.0, [M+2]⁻.

Example 21(3S)-3-(4-((3-(2-(Trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 21

(A) (3S)-Ethyl3-(4-((3-(2-(trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from 2-(trifluoromethyl)phenylboronic acid and (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) following General Procedure A, using PdCl₂(dppf).CH₂Cl₂ asthe palladium catalyst and Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd.for C₃₀H₂₅F₃O₃S: 522.58, found: 523.1 [M+H]⁺.

(B)(3S)-3-(4-((3-(2-(Trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 21) was prepared from (3S)-ethyl3-(4-((3-(2-(trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOH,2N HCl for reaction acidification and a reaction temperature of 30° C.overnight. ¹H NMR (DMSO-d₆) δ 8.08 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.6 Hz,1H), 7.69-7.82 (m, 3H), 7.48-7.51 (m, 2H), 7.43 (s, 1H), 7.24 (d, J=8.8Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 5.13 (s, 2H), 3.91-3.93 (m, 1H),2.58-2.67 (m, 2H), 1.77 (s, 3H). LC/MS: mass calcd. for C₂₈H₂₁F₃O₃S:494.52, found: 493.1 [M−H]⁻.

Example 22(3S)-3-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 22

(A) (3S)-Ethyl3-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and (2-methylpyridin-3-yl)boronic acid following GeneralProcedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst andCs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₂₉H₂₇NO₃S: 469.59,found: 470.2 [M+H]⁺.

(B)(3S)-3-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 22) was prepared from (3S)-ethyl3-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C using LiOH as base, EtOH in place of MeOHand 2N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 12.24 (s, 1H),8.56 (dd, J=1.6, 4.8 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.68(dd, J=1.6, 7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.34-7.38(m, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.18 (s, 2H),3.90-3.92 (m, 1H), 2.56 (d, J=7.6 Hz, 2H), 2.29 (s, 3H), 1.77 (s, 3H).LC/MS: mass calcd. for C₂₇H₂₃NO₃S: 441.54, found: 442.1 [M+H]⁺.

Example 23(3S)-3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid, Cpd 23

(A) To an ice-cold solution of 1-benzothiophen-5-ol (4.2 g, 27.96 mmol)in pyridine (50 mL) was added acetyl chloride (2.4 g, 30.57 mmol) indrop-wise fashion. The resulting solution was allowed to stir at rt for2 h. The reaction was then quenched by the addition of water (50 mL) andthe resulting solution was extracted with ethyl acetate (3×50 mL) andthe organic layers combined and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel chromatography (0-10%EtOAc/petroleum ether) to obtain benzo[b]thiophen-5-yl acetate as awhite solid (4.8 g, 89% yield). LC/MS: Calcd. for C₁₀H₈O₂S: 192.23,found: 193.0 [M+H]⁺.

(B) To a solution of benzo[b]thiophen-5-yl acetate (5.8 g, 30.17 mmol)in AcOH (30 mL) was added a solution of Br₂ (5.3 g, 33.16 mmol) in AcOH(70 mL) in dropwise fashion and the resulting solution was stirred at rtfor 1 h. Water (100 mL) was then added and the resulting solution wasextracted with ethyl acetate (3×100 mL). The combined organic extractswere concentrated under reduced pressure and the residue thus obtainedwas purified by silica gel chromatography (0-10% EtOAc/petroleum ether)to provide 3-bromobenzo[b]thiophen-5-yl acetate as a white solid (3 g,37% yield). LC/MS: Calcd. for C₁₀H₇BrO₂S: 271.13, found: 270.9 [M⁺],272.9 [M+2]⁺.

(C) A mixture of 3-bromo-1-benzo[b]thiophen-5-yl acetate (203 mg, 0.75mmol) and K₂CO₃ (516 mg, 3.73 mmol) in methanol (20 mL) and water (2 mL)was stirred at rt for 2 h. The reaction was then quenched by theaddition of satd. aq. NH₄Cl (30 mL) and the resulting solution wasextracted with ethyl acetate (3×10 mL). The combined organic extractswere dried (Na₂SO₄) and concentrated under reduced pressure to afford3-bromo-1-benzo[b]thiophen-5-ol as a white solid (172 mg, crude) thatwas used directly without further purification. ¹H NMR (CDCl₃) δ7.69-7.71 (m, 1H), 7.45 (s, 1H), 7.24 (s, 1H), 7.98-7.00 (m, 1H).

(D) To an ice-cooled solution of (3S)-ethyl3-(4-hydroxyphenyl)hex-4-ynoate (5.2 g, 22.39 mmol) (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708) andtriethylamine (6.8 g, 67.20 mmol) in DCM (200 mL) was addedtrifluoromethanesulfonic anhydride (7.55 g, 26.76 mmol) in drop-wisefashion. After stirring for 2 h at rt, the reaction was then quenched bythe addition of 400 mL of satd. aq. NaHCO₃. The resulting solution wasextracted with DCM (2×200 mL) and the combined organic extracts weredried (Na₂SO₄) and concentrated under reduced pressure to afford(3S)-ethyl 3-(4-(trifluoromethylsulfonyloxy)phenyl)hex-4-ynoate as darkred oil (8.1 g, crude), which was used directly without furtherpurification.

(E) To a mixture of (3S)-ethyl3-(4-(trifluoromethylsulfonyloxy)phenyl)hex-4-ynoate (8.1 g, 22.23mmol), Pd₂(dba)₃ (2 g, 2.18 mmol), RuPhos (2.6 g, 5.5 mmol) and (Na₂CO₃)(4.7 g, 44.34 mmol) in dioxane (200 mL) and water (20 mL) was addedpotassium acetoxymethyltrifluoroborate (8 g, 41.24 mmol). The resultingsolution was stirred for 30 min at 50° C. and then for 3 h at 100° C.After cooling to rt, water (1 L) was added and the resulting solutionwas extracted with EtOAc (2×1 L) of ethyl acetate and the combinedorganic extracts were concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (0-10% ethylacetate/petroleum ether) to afford (3S)-ethyl3-(4-(hydroxymethyl)phenyl)hex-4-ynoate (2.6 g, 46%) as a pale yellowoil. ¹H NMR (DMSO-d₆) δ 7.24-7.33 (m, 4H), 5.14 (t, J=5.7 Hz, 1H), 4.46(d, J=5.7 Hz, 2H), 3.99-4.09 (m, 3H), 2.70 (d, J=7.5 Hz, 2H), 1.77 (s,3H), 1.15 (t, J=3.0 Hz, 3H).

(F) (3S)-Ethyl3-(4-(((3-bromobenzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoate wasprepared from 3-bromo-1-benzo[b]thiophen-5-ol and (3S)-ethyl3-(4-(hydroxymethyl)phenyl)hex-4-ynoate following General Procedure Busing (Bu)₃P and ADDP at a reaction temperature of 50° C. for 3 h.LC/MS: Calcd. for C₂₃H₂₁BrO₃S: 457.38, found: 457.1 [M]⁺, 459.0 [M+2]⁺.

(G) (3S)-Ethyl3-(4-(((3-(2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-(((3-bromobenzo[b]thiophen-5-yl)oxy)methyl)-phenyl)hex-4-ynoate and(2-methylphenyl)boronic acid following General Procedure A, usingPdCl₂(dppf). CH₂Cl₂ as the palladium catalyst, Cs₂CO₃ in place of K₂CO₃and a reaction temperature of 80° C. for 2 h. LC/MS: Calcd. forC₃₀H₂₈O₃S: 468.61, found: 469.2 [M+H]⁺.

(H)(3S)-3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid (Cpd 23) was prepared from (3S)-ethyl3-(4-(((3-(2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a reaction temperature of 30° C. overnight and 2N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 7.94 (d, J=8.8 Hz, 1H), 7.66 (s, 1H),7.28-7.41 (m, 7H), 7.20 (d, J=7.6 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 6.80(s, 1H), 5.02 (s, 2H), 3.98-4.03 (m, 1H), 2.60-2.67 (m, 2H), 2.02 (s,3H), 1.79 (s, 3H); LC/MS: Calcd. for C₂₈H₂₄O₃S: 440.55, found: 439.0[M−H]⁻.

Example 24(3S)-3-(4-(((3-(2-Methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid, Cpd 24

(A) To a mixture of 4-bromo-3-methylphenol (1 g, 5.35 mmol) and K₂CO₃(1.1 g, 7.96 mmol) in DMF (10 mL) was added 3-(methylsulfonyl)propyl4-methylbenzenesulfonate (1.72 g, 5.88 mmol) and the resultant mixturewas stirred at 80° C. for 2 h. After cooling to rt, satd. aq. NH₄Cl (10mL) was added and the resultant solution was extracted with EtOAc (3×20mL). The combined organic extracts were concentrated under reducedpressure and the residue thus obtained was purified by silica gelchromatography (0-30% ethyl acetate/petroleum ether) to afford1-bromo-4-(3-methanesulfonylpropoxy)-2-methylbenzene (1.5 g, 91%) as awhite solid. ¹H NMR (CDCl₃) δ 7.40 (d, J=8.7 Hz, 1H), 6.78 (d, J=2.7 Hz,1H), 6.59 (dd, J=3.0, 8.7 Hz, 1H), 4.06-4.16 (m, 2H), 3.24 (t, J=7.8 Hz,2H), 2.95 (s, 3H), 2.29-2.38 (m, 5H).

(B)2-[4-(3-Methanesulfonylpropoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared from 1-bromo-4-(3-methanesulfonylpropoxy)-2-methylbenzeneand bis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and KOAc in place of K₂CO₃at a reaction temperature of 90° C. overnight. LC/MS: mass calcd. forC₁₇H₂₇BO₅S: 354.3, found: 355.3 [M+H]⁺.

(C) (3S)-Ethyl3-(4-(((3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-(((3-bromobenzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoate(from Example 23F) and2-[4-(3-methanesulfonylpropoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefollowing General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst, Cs₂CO₃ in place of K₂CO₃ and a reaction temperature of 80° C.for 2 h. LC/MS: Calcd. for C₃₄H₃₆O₆S₂: 604.78, found: 605.2 [M]⁺.

(D) (3S)-3-(4-(((3-(2-Methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid (Cpd 24) was prepared from (3S)-ethyl3-(4-(((3-(2-methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a reaction temperature of 30° C. overnight and 2N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 7.92 (d, J=7.6 Hz, 1H), 7.59 (s, 1H),7.33-7.38 (m, 4H), 7.10-7.14 (m, 1H), 6.81-6.95 (m, 3H), 5.03 (s, 2H),4.15 (t, J=6.0 Hz, 2H), 3.98-4.03 (m, 1H), 3.31 (t, J=7.6 Hz, 2H), 3.04(s, 3H), 2.66 (d, J=8.0 Hz, 2H), 2.15-2.22 (m, 2H), 2.00 (s, 3H), 1.88(s, 3H). LC/MS: Calcd. for C₃₂H₃₂O₆S₂: 576.72, found: 575.0 [M−H]⁻.

Example 25(3S)-3-(4-(((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)-benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid, Cpd 25

(A)(3S)-3-{4-[({3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl]-1-benzothiophen-5-yl}oxy)methyl]phenyl}hex-4-ynoatewas prepared from (3S)-ethyl3-(4-(((3-bromobenzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoate(from Example 23F) and4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide (from Example 6C) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₃₅H₃₄O₅S₂: 598.77, found 599.1 [M]⁺.

(B)(3S)-3-(4-(((3-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)-benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid (Cpd 25) wasprepared from(3S)-3-{4-[({3[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl]-1-benzothiophen-5-yl}oxy)methyl]phenyl}hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a reaction temperature of 30° C. overnight and 2N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.27 (br. s, 1H), 7.94 (d, J=8.8 Hz,1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.32-7.39 (m, 5H), 7.21 (d, J=8.0 Hz,1H), 7.13 (dd, J=2.4, 8.8 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.09 (d,J=4.4 Hz, 1H), 5.03 (s, 2H), 3.94-4.03 (m, 3H), 3.37-3.40 (m, 2H),3.11-3.12 (m, 2H), 2.64 (d, J=7.6 Hz, 2H), 2.05 (s, 3H), 1.78 (s, 3H).LC/MS: Calcd. for C₃₃H₃₀O₅S₂: 570.72, found: 569.0 [M−H]⁻.

Example 26(3S)-3-(4-(((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid, Cpd 26

(A) A mixture of4-(4-bromo-3-methylphenyl)-3,6-dihydro-2H-thiopyran-1,1-dioxide (301 mg,1.00 mmol) (from Example 6B) and PtO₂ (23 mg, 0.1 mmol) in ethyl acetate(10 mL) was hydrogenated at rt at a pressure of about 50 psi overnight.The mixture was then filtered and the filtrate was concentrated underreduced pressure to afford4-(4-bromo-3-methylphenyl)tetrahydro-2H-thiopyran 1,1-dioxide as a whitesolid (290 mg, 96%). ¹H NMR (CDCl₃) δ 7.48 (d, J=8.1 Hz, 1H), 7.08-7.10(m, 1H), 6.91 (d, J=8.1 Hz, 1H), 3.12-3.15 (m, 4H), 2.68-2.76 (m, 1H),2.31-2.45 (m, 5H), 2.16-2.21 (m, 2H).

(B)4-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-thiopyran1,1-dioxide was prepared from4-(4-bromo-3-methylphenyl)tetrahydro-2H-thiopyran 1,1-dioxide andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dPPf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ anddioxane as solvent. LC/MS: mass calcd. for C₁₈H₂₇BO₄S: 350.28, found351.2 [M+H]⁺.

(C) (3S)-Ethyl3-(4-(((3-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatewas prepared from4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-thiopyran1,1-dioxide and (3S)-ethyl3-(4-(((3-bromobenzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoate(from Example 23F) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₃₅H₃₆O₅S₂: 600.79, found 601.2 [M]⁺.

(D)(3S)-3-(4-(((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo-[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid (Cpd 26) was prepared from (3S)-ethyl3-(4-(((3-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a reaction temperature of 30° C. overnight and 2N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 7.93 (d, J=8.8 Hz, 1H), 7.63 (s, 1H),7.32-7.37 (m, 4H), 7.25 (s, 1H), 7.11-7.18 (m, 3H), 6.81 (d, J=2.4 Hz,1H), 5.03 (s, 2H), 4.00-4.01 (m, 1H), 3.35-3.40 (m, 2H), 3.13-3.16 (m,2H), 2.95-3.05 (m, 1H), 2.64 (d, J=7.6 Hz, 2H), 2.16-2.20 (m, 4H), 2.03(s, 3H), 1.78 (s, 3H). LC/MS: Calcd. for C₃₃H₃₂O₅S₂: 572.73, found:571.0 [M−H]⁻.

Example 27(3S)-3-(4-(((3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid, Cpd 27

(A) A mixture of (3S)-ethyl3-(4-(((3-bromobenzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoate (150mg, 0.33 mmol) (from Example 23F), (2,6-dimethylphenyl)boronic acid (150mg, 1.00 mmol), Pd₂(dba)₃ (12 mg, 0.01 mmol), SPhos (22 mg, 0.05 mmol)and K₃PO₄ (212 mg, 1.00 mmol) in toluene (2 mL) was stirred at 100° C.in a sealed tube for 2 h. After cooling to rt, water (15 mL) was addedand the mixture was extracted with EtOAc (3×10 mL). The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (0-5% EtOAc/petroleum ether) to provide (3S)-ethyl3-(4-(((3-(2,6-dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoateas yellow oil (80 mg, 51% yield). LC/MS: Calcd. for C₃₁H₃₀O₃S: 482.63,found: 483.2 [M±H]⁺.

(B) (3S)-3-(4-(((3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid (Cpd 27) was prepared from (3S)-ethyl3-(4-(((3-(2,6-dimethylphenyl)benzo[b]-thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, and 2N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 7.94 (d,J=9.0 Hz, 1H), 7.56 (s, 1H), 7.23-7.35 (m, 5H), 7.09-7.18 (m, 3H), 6.57(d, J=2.4 Hz, 1H), 4.98 (s, 2H), 3.96-4.02 (m, 1H), 2.63 (d, J=7.5 Hz,1H), 1.89 (s, 3H), 1.88 (s, 3H), 1.78 (s, 3H). LC/MS: Calcd. forC₂₉H₂₆O₃S: 454.58, found: 453.1 [M−H]⁻.

Example 282-(1-(4-((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid, Cpd 28

(A) To an ice-cold solution of 3-acetoxycyclobutanone (2.563 g, 20 mmol)in anhydrous DCM (100 mL) was added ethyl triphenylphosphoranylideneacetate (9.06 g, 26 mmol) and the resulting mixture was stirred at rtfor 18 h. The reaction was then concentrated under reduced and theresultant residue was purified by silica gel chromatography (0-20%EtOAc/heptanes) to provide ethyl 2-(3-acetoxycyclobutylidene)acetate(2.15 g, 54%) as a slightly yellowish oil. LC/MS: Calcd. for C₁₀H₁₄O₄:198.22, found: 199.1 [M±H]⁺.

(B) To a solution of chloro(1,5-cyclooctadiene)rhodium(I) dimer (197 mg,0.4 mmol) in dioxane (20 mL) under a nitrogen atmosphere at was added 1NNaOH (14 mL, 14 mmol) was added 4-hydroxyphenylboronic acid (2.206 g, 16mmol), followed by a solution of ethyl2-(3-acetoxycyclobutylidene)acetate (1.586 g, 8 mmol) in dioxane (6 mL),and the mixture was heated at 50° C. for 1 h. After cooling to rt, thereaction was poured into a mixture of EtOAc (60 mL) and water (60 mL)and 2N HCl was then added to acidify the aqueous phase to a pH of 4.After phase separation, the aqueous phase was extracted with EtOAc (2×10mL) and the combined extracts were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification of the resultantresidue by silica gel chromatography (20-60% EtOAc/heptanes) to provideethyl 2-[3-acetoxy-1-(4-hydroxyphenyl)cyclobutyl]acetate as mixture ofsyn- and anti-isomers, that was used as such. LC/MS: Calcd. forC₁₆H₂₀O₅: 292.33, found: 315.0 [M+Na]⁺.

(C) A mixture of ethyl2-[3-acetoxy-1-(4-hydroxyphenyl)cyclobutyl]acetate (1.0 g, 3.42 mmol)and K₂CO₃ (1.89 g, 13.68 mmol) in EtOH (20 mL) was stirred at 40° C.overnight, then concentrated under reduced pressure. The residue thusobtained was partitioned between EtOAc (30 mL) and water (30 mL), andtreated with 2N HCl to acidify the aqueous phase to pH 5-6. After phaseseparation, the aqueous phase was extracted with EtOAc (30 mL) and thecombined extracts were dried (Na₂SO₄), filtered, and concentrated underreduced pressure. Purification of the resultant residue by silica gelchromatography (20-60% EtOAc/heptanes) to provide ethyl2-[3-hydroxy-1-(4-hydroxyphenyl)cyclobutyl]acetate as mixture of syn-and anti-isomers, that was used as such. LC/MS: Calcd. for C₁₄H₁₈O₄:250.29, found: 251.1 [M+H]⁺, 273.0 [M+Na]⁺.

(D) To a solution of ethyl2-[3-hydroxy-1-(4-hydroxyphenyl)cyclobutyl]acetate (745 mg, 2.98 mmol)in DCM (15 mL) and DMSO (5 mL) was added DIEA (3.08 mL, 17.86 mmol)followed by sulfur trioxide-pyridine complex (1.895 g, 11.91 mmol) andthe resultant mixture was stirred at rt for 2 h. The mixture was thenpartitioned between EtOAc (60 mL) and water (60 mL), and treated with 2NHCl to acidify the aqueous phase to pH 3-4. After phase separation, theaqueous phase was extracted with EtOAc (50 mL) and the combined extractswere washed with water (80 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification of the resultantresidue by silica gel chromatography (5-20% EtOAc/DCM) to provide ethyl2-(1-(4-hydroxyphenyl)-3-oxocyclobutyl)acetate (537 mg, 73%) as acolorless oil. LC/MS: Calcd. for C₁₄H₁₆O₄: 248.28, found: 249.1 [M+H]⁺.

(E) Ethyl2-(1-(4-((3-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatewas prepared from ethyl 2-(1-(4-hydroxyphenyl)-3-oxocyclobutyl)acetateand4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide (from Example 6D) following General Procedure B, using Ph₃Pand DBAD. LC/MS: Calcd. for C₃₅H₃₄O₆S₂: 614.78, found: 615.1 [M]⁺, 637.2[M+Na]⁺.

(F)2-(1-(4-((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (Cpd 28) was prepared from ethyl2-(1-(4-((3-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatefollowing General Procedure C, using LiOH as base and 2N HCl forreaction acidification. ¹H NMR (CDCl₃) δ 7.94 (d, 1H), 7.40-7.50 (m,2H), 7.28-7.36 (m, 3H), 7.23 (d, J=8.6 Hz, 3H), 6.92 (d, J=8.6 Hz, 2H),5.95 (t, J=4.3 Hz, 1H), 5.10 (s, 2H), 3.81-3.88 (m, 2H), 3.37-3.57 (m,4H), 3.16-3.33 (m, 4H), 2.91 (s, 2H), 2.16 (s, 3H). LC/MS: Calcd. forC₃₃H₃₀O₆S₂: 586.73, found: 587.3 [M±H]⁺.

Example 292-(1-(4-((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid, Cpd 29

(A) To a mixture of4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)-3,6-dihydro-2H-thiopyran1,1-dioxide (from Example 6D) and Pd/C (10% wt, 80 mg, 0,075 mmol) inEtOH (6 mL) under nitrogen was added a solution of ammonium formate (472mg, 7.5 mmol) in water (1 mL), and the resultant mixture was stirred at50° C. for 5 h. After cooling to rt, the mixture was diluted with EtOAc(10 mL) and filtered. The filtered solids were washed with EtOAc (30 mL)and the combined filtrate and washings were concentrated. EtOAc (2 mL)and water (20 mL) were added, followed by heptanes (30 mL). Theresultant solid thus obtained was filtered, washed successively withwater (3×5 mL) and heptanes (5 mL) and dried to provide4-(4-(5-(hydroxymethyl)benzo[b]-thiophen-3-yl)-3-methylphenyl)tetrahydro-2H-thiopyran1,1-dioxide (136 mg, 70%) which was used directly without furtherpurification.

(B) Ethyl2-(1-(4-((3-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatewas prepared from4-(4-(5-(hydroxymethyl)benzo[b]-thiophen-3-yl)-3-methylphenyl)tetrahydro-2H-thiopyran1,1-dioxide and ethyl 2-(1-(4-hydroxyphenyl)-3-oxocyclobutyl)acetate(from Example 28D) following General Procedure B, using Ph₃P and DBAD.¹H NMR (CDCl₃) δ 7.94 (d, J=9.1 Hz, 1H), 7.41-7.50 (m, 2H), 7.27-7.35(m, 2H), 7.20 (d, J=8.6 Hz, 3H), 7.14 (d, J=8.1 Hz, 1H), 6.92 (d, J=8.6Hz, 2H), 5.10 (s, 2H), 3.99 (q, J=7.4 Hz, 2H), 3.46 (s, 4H), 3.10-3.25(m, 4H), 2.83 (s, 3H), 2.38-2.60 (m, 2H), 2.23-2.38 (m, 2H), 2.15 (s,3H), 1.11 (t, J=7.1 Hz, 3H).

(C)2-(1-(4-((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (Cpd 29) was prepared from ethyl2-(1-(4-((3-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatefollowing General Procedure C, using LiOH as base, MeCN in place of THF,a reaction temperature of 50° C. for 3 h, and 2N HCl for reactionacidification. ¹H NMR (CDCl₃) δ 7.93 (d, 1H), 7.38-7.47 (m, 2H), 7.30(s, 1H), 7.23 (dd, J=8.1, 2.5 Hz, 3H), 7.18 (s, 1H), 7.12 (dd, J=7.6,1.5 Hz, 1H), 6.91 (d, J=9.1 Hz, 2H), 5.12 (s, 2H), 3.39-3.55 (m, 4H),3.11-3.24 (m, 4H), 2.92 (s, 2H), 2.76-2.88 (m, 1H), 2.38-2.56 (m, 2H),2.23-2.35 (m, 2H), 2.12 (s, 3H). LC/MS: Calcd. for C₃₃H₃₂O₆S₂: 588.75,found: 589.0 [M]⁺.

Example 302-(3-Oxo-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid, Cpd 30

(A) Ethyl2-(3-acetoxy-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetatewas prepared from 5-hydroxymethyl-3-(2-methylphenyl)benzo[b]-thiophene(from Example 1B) ethyl 2-(1-(4-hydroxyphenyl)-3-oxocyclobutyl)acetate(from Example 28D) following General Procedure B using PBu₃ and ADDP intoluene as solvent (in place of THF) at 60° C. for 2 h. ¹H NMR (CDCl₃) δ7.92-7.94 (m, 1H), 7.45-7.47 (m, 2H), 7.17-7.37 (m, 7H), 6.89-6.94 (m,2H), 5.09 (s, 2H), 3.99 (dd, J=7.2, 14.4 Hz, 2H), 3.46 (s, 4H), 2.82 (s,2H), 2.16 (s, 3H), 1.10 (t, J=7.2 Hz, 3H).

(B)2-(3-Oxo-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-cyclobutyl)aceticacid (Cpd 30) was prepared from ethyl2-(3-acetoxy-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (CD₃OD) δ 7.97 (d, J=8.1Hz, 1H), 7.26-7.50 (m, 9H), 6.93-6.97 (m, 2H), 5.17 (s, 2H), 3.41-3.56(m, 4H), 2.82 (s, 2H), 2.10 (s, 3H)⁻. LC/MS: mass calcd. for C2₈H₂₄O₄S:456.56, found 455.2 [M−H]⁻.

Example 312-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid, Cpd 31

2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid (Cpd 31) was prepared from2-(3-oxo-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-cyclobutyl)aceticacid (from Example 30) following General Procedure G. ¹H NMR (CD₃OD) δ7.93 (d, J=8.1 Hz, 1H), 7.22-7.46 (m, 9H), 6.85-6.88 (m, 2H), 5.12 (s,2H), 3.88-3.93 (m, 1H), 2.76-2.83 (m, 2H), 2.57 (s, 2H), 2.24-2.31 (m,2H), 2.07 (s, 3H). LC/MS: mass calcd. for C₂₈H₂₆O₄S: 456.56, found 457.1[M]⁻.

Example 322-(1-(4-((3-(4-(2-Ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid, Cpd 32

(A) A mixture of 4-bromo-3-methylphenol (10 g, 53.47 mmol),1-bromo-2-ethoxyethane (10.62 g, 69.40 mmol) and K₂CO₃ (11.13 g, 79.95mmol) in DMF (100 mL) was stirred overnight at 75° C. After cooling tort, brine (250 mL) was added and the mixture was extracted with EtOAc(4×100 mL). The combined organic extracts were washed with brine (4×100mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure.Purification of the resultant residue by silica gel chromatography (5%EtOAc/petroleum ether afforded1-bromo-4-(2-ethoxyethoxy)-2-methylbenzene (12.25 g, 88%) as lightyellow oil which was used directly.

(B)2-[4-(2-Ethoxyethoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared from 1-bromo-4-(2-ethoxyethoxy)-2-methylbenzene andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and KOAc in place of K₂CO₃at a reaction temperature of 100° C. overnight. LC/MS: mass calcd. forC₁₈H₂₇BO₄: 306.20, found: 307.1 [M+H]⁺.

(C) Ethyl2-(1-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatewas prepared from 3-bromo-5-hydroxymethylbenzothiophene (from Example1A) and ethyl 2-(1-(4-hydroxyphenyl)-3-oxocyclobutyl)acetate (fromExample 28D) following General Procedure B using PBu₃ and ADDP intoluene as solvent (in place of THF). LC/MS: mass calcd. forC₂₃H₂₁BrO4S: 473.38, found 473.1 [M]⁺, 475.0 [M+2]⁺.

(D) Ethyl2-(1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatewas prepared from ethyl2-(1-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetateand2-(4-(2-ethoxyethoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefollowing General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst, DMF as solvent at a reaction temperature of 60° C. overnight.LC/MS: mass calcd. for C₃₄H₃₆O₆S: 572.71, found 573.4 [M+H]⁺, 595.4[M+Na]⁺.

(E)2-(1-(4-((3-(4-(2-Ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (Cpd 32) was prepared from ethyl2-(1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatefollowing General Procedure C, using NaOH (10 eq.) as base, MeCN/H₂O(4:1 v/v) as solvent and 1N HCl for reaction acidification. Productpurification was accomplished by silica gel chromatography (0-80% EtOAcin petroleum ether). ¹H NMR (DMSO-d₆) δ 8.06 (d, J=8.4 Hz, 1H), 7.64 (s,1H), 7.44-7.52 (m, 1H), 7.42 (s, 1H), 7.15-7.26 (m, 3H), 6.86-6.96 (m,4H), 5.17 (s, 2H), 4.13-4.15 (m, 2H), 3.71-3.74 (m, 2H), 3.53 (dd,J=7.2, 14.0 Hz, 2H), 3.27-3.41 (m, 4H), 2.80 (s, 2H), 2.05 (s, 3H), 1.15(t, J=7.2 Hz, 3H). LC/MS: mass calcd. for C₃₂H₃₂O₆S: 543.66, found 543.1[M]⁻.

Example 332-(1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid, Cpd 33

(A) 4-(4-Bromo-3-methylphenoxy)tetrahydro-2H-thiopyran 1,1-dioxide wasprepared from 4-bromo-3-methylphenol and4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide following General ProcedureB, using DBAD and Ph₃P at a reaction temperature of 50° C. overnight. ¹HNMR (CDCl₃) δ 7.43 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.0 Hz, 1H), 6.64 (dd,J=2.7, 8.7 Hz, 1H), 4.59-4.61 (m, 1H), 3.33-3.43 (m, 2H), 2.90-2.96 (m,2H), 2.30-2.48 (m, 7H).

(B)4-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)tetrahydro-2H-thiopyran1,1-dioxide was prepared from4-(4-bromo-3-methylphenoxy)tetrahydro-2H-thiopyran 1,1-dioxide andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, and KOAc in place of K₂CO₃using dioxane as solvent at a reaction temperature of 100° C. overnight.¹H NMR (CDCl₃) δ 7.73 (d, J=7.6 Hz, 1H), 6.70-6.73 (m, 2H), 4.65-4.75(m, 1H), 3.36-3.44 (m, 2H), 2.89-2.93 (m, 2H), 2.52 (s, 3H), 2.44-2.49(m, 2H), 2.32-2.38 (m, 2H), 1.27 (s, 12H).

(C) Ethyl2-(1-(4-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatewas prepared from ethyl2-(1-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetate(from Example 32C) and4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)tetrahydro-2H-thiopyran1,1-dioxide following General Procedure A, using PdCl₂(dppf).CH₂Cl₂ asthe palladium catalyst, DMF as solvent at a reaction temperature of 80°C. overnight. LC/MS: mass calcd. for C₃₅H₃₆O₇S₂: 632.79, found 655.4[M+Na]⁺.

(D)2-(1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid was prepared from ethyl2-(1-(4-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatefollowing General Procedure C, using NaOH as base, MeCN in place of THFand 1N HCl for reaction acidification. Product purification wasaccomplished by silica gel chromatography (50% EtOAc in petroleumether). ¹H NMR (CD₃OD) δ 7.94 (d, J=8.1 Hz, 1H), 7.46-7.38 (m, 3H),7.28-7.25 (m, 2H), 7.20-7.17 (m, 1H), 6.96-6.95 (m, 1H), 6.93-6.87 (m,3H), 5.147 (s, 2H), 4.79-4.78 (m, 1H), 3.54-3.32 (m, 6H), 3.10-3.05 (m,2H), 2.81 (s, 2H), 2.49-2.32 (m, 4H), 2.06 (s, 3H). LC/MS: mass calcd.for C₃₃H₃₂O₇S₂: 604.73, found 622.1 [M+NH₃]⁺.

Example 342-(1-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid, Cpd 34

(A) Ethyl2-[1-[4-([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)phenyl]-3-oxocyclobutyl]acetatewas prepared from4,4,5,5-tetramethyl-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,3,2-dioxaborolane(from Example 15B) and ethyl2-(1-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetate(from Example 32C) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, DMF as solvent at areaction temperature of 80° C. overnight. LC/MS: mass calcd. forC₃₅H₃₆O₆S: 584.72, found 607.4 [M+Na]⁺.

(B)2-(1-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (Cpd 34) was prepared from ethyl2-[1-[4-([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)phenyl]-3-oxocyclobutyl]acetatefollowing General Procedure C, using NaOH as base, MeCN in place of THFand 1N HCl for reaction acidification. Product purification wasaccomplished by silica gel chromatography (50% EtOAc in petroleumether). ¹H NMR (CD₃OD) δ 7.93 (d, J=8.1 Hz, 1H), 7.46-7.37 (m, 3H),7.28-7.25 (m, 2H), 7.17-7.14 (m, 1H), 6.93-6.86 (m, 4H), 5.14 (s, 2H),4.70-4.60 (m, 1H), 4.02-3.95 (m, 2H), 3.67-3.59 (m, 2H), 3.52-3.35 (m,4H), 2.81 (s, 2H), 2.10-2.05 (m, 5H), 1.82-1.80 (m, 2H). LC/MS: masscalcd. for C₃₃H₃₂O₆S: 556.67, found 557.1 [M+H]⁺, 574.2 [M+NH₃]⁺.

Example 352-((1r,3r)-3-Hydroxy-1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid, Cpd 35

2-((1r,3r)-3-Hydroxy-1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid (Cpd 35) was prepared from2-(1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (from Example 32) following General Procedure G. ¹H NMR (CD₃OD) δ7.95 (d, J=8.1 Hz, 1H), 7.48-7.39 (m, 3H), 7.30-7.27 (m, 2H), 7.19-7.16(m, 1H), 6.95-6.86 (m, 4H), 5.14 (s, 2H), 4.20-4.17 (m, 2H), 3.96-3.93(m, 1H), 3.86-3.82 (m, 2H), 3.65 (dd, J=7.2, 14.1 Hz, 2H), 2.85-2.79 (m,2H), 2.61 (s, 2H), 2.35-2.28 (m, 2H), 2.08 (s, 3H), 1.26 (t, J=7.2 Hz,3H). LC/MS: mass calcd. for C₃₂H₃₄O₆S: 546.67, found 547.4 [M+H]⁺.

Example 362-((1r,3r)-1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-hydroxycyclobutyl)aceticacid, Cpd 36

2-((1r,3r)-1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-hydroxycyclobutyl)aceticacid (Cpd 36) was prepared from2-(1-(4-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (from Example 33D) following General Procedure G. ¹H NMR (CD₃OD) δ7.94 (d, J=8.4 Hz, 1H), 7.47-7.39 (m, 3H), 7.28-7.18 (m, 3H), 7.01-6.87(m, 4H), 5.14 (s, 2H), 4.81-4.79 (m, 1H), 3.97-3.92 (m, 1H), 3.39-32 (m,2H), 3.32-3.06 (m, 2H), 2.83-2.79 (m, 2H), 2.62 (s, 2H), 2.45-2.29 (m,6H), 2.07 (s, 3H). LC/MS: mass calcd. for C₃₃H₃₄O₇S₂: 606.75, found605.0 [M−H]⁻.

Example 372-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid, Cpd 37

2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid (Cpd 37) was prepared from2-(1-(4-((3-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (from Example 34B) following General Procedure G. ¹H NMR (CD₃OD) δ7.94 (d, J=8.4 Hz, 1H), 7.48-7.42 (m, 3H), 7.38-7.28 (m, 2H), 7.19-7.16(m, 1H), 6.95-6.87 (m, 4H), 5.14 (s, 2H), 4.68-4.63 (m, 1H), 4.04-3.98(m, 2H), 3.97-3.90 (m, 1H), 3.68-3.60 (m, 2H), 2.80-2.76 (m, 2H), 2.51(s, 2H), 2.40-2.33 (m, 2H), 2.12-2.07 (m, 5H), 1.81-1.75 (m, 2H). LC/MS:mass calcd. for C₃₃H₃₄O₆S: 558.68, found 557.0 [M−H]⁻.

Example 382-(1-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid, Cpd 38

(A) Ethyl2-(1-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatewas prepared from ethyl2-(1-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetate(from Example 32C) and (2-methylpyridin-3-yl)boronic acid followingGeneral Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalystand DMF as solvent at a reaction temperature of 60° C. overnight. LC/MS:mass calcd. for C₂₉H₂₇NO₄S: 485.59, found: 486.3 [M+H]⁺.

(B)2-(1-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (Cpd 38) was prepared from ethyl2-(1-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatefollowing General Procedure C, using NaOH as base, MeCN in place of THFand 1N HCl for reaction acidification. Product purification wasaccomplished by silica gel chromatography (0-10% MeOH in DCM). ¹H NMR(CD₃OD) δ 8.53-8.51 (m, 1H), 8.03-8.00 (m, 1H), 7.77-7.74 (m, 1H), 7.62(s, 1H), 7.54-7.51 (m, 1H), 7.43-7.39 (m, 2H), 7.30-7.26 (m, 2H),6.97-6.93 (m, 2H), 5.20 (s, 2H), 3.50-3.41 (m, 4H), 2.86 (s, 2H), 2.33(s, 3H). LC/MS: mass calcd. for C₂₇H₂₃NO₄S: 457.54, found: 458.2 [M+H]⁺.

Example 392-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid, Cpd 39

2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid (Cpd 39) was prepared from2-(1-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (from Example 38) following General Procedure G. ¹H NMR (DMSO-d₆) δ8.56-8.54 (m, 1H), 8.11-8.09 (m, 1H), 7.84 (s, 1H), 7.68-7.66 (m, 1H),7.52-7.50 (m, 1H), 7.43 (s, 1H), 7.37-7.33 (m, 1H), 7.22-7.20 (m, 2H),6.88-6.85 (m, 2H), 5.15 (s, 2H), 3.79-3.77 (m, 1H), 2.64-2.62 (m, 2H),2.51-2.50 (m, 2H), 2.28 (s, 3H), 2.17-2.15 (m, 2H). LC/MS: mass calcd.for C₂₇H₂₅NO₄S: 459.56, found: 458.0 [M−H]⁻.

Example 402-(1-(4-((3-(4-(1,1-Dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid, Cpd 40

(A) To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (40.0 g,233.65 mmol) in DCM (1 L) was added(triphenylphosphoranylidene)acetaldehyde (80 g, 262.88 mmol, 1.13 equiv)in several batches. After stirring at 40° C. overnight, the mixture wasconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (5-10% EtOAc/petroleum ether) toprovide tert-butyl 3-(2-oxoethylidene)azetidine-1-carboxylate (45.8 g,99%) as a colorless oil. ¹H NMR (CDCl₃) δ 9.61 (d, J=6.3 Hz, 1H), 4.92(d, J=2.4 Hz, 2H), 4.71 (d, J=2.4 Hz, 2H), 1.47 (s, 9H).

(B) A solution of tert-butyl 3-(2-oxoethylidene)azetidine-1-carboxylate(45.8 g, 232.2 mmol), piperidine (1.38 g, 16.2 mmol), and thioaceticacid (26.5 g, 348.7 mmol) in THF (1 L) was stirred overnight at rt. Themixture was then concentrated under reduced pressure and the residuethus obtained was purified by silica gel chromatography (10-25%EtOAc/petroleum ether) to provide tert-butyl3-(acetylsulfanyl)-3-(2-oxoethyl)azetidine-1-carboxylate (43 g, 68%) asa yellow oil. ¹H NMR (CDCl₃) δ 9.69 (s, 1H), 4.04-4.09 (m, 4H), 3.30 (s,2H), 2.30 (s, 3H), 1.47 (s, 9H).

(C) To an ice-cooled solution of tert-butyl3-(acetylsulfanyl)-3-(2-oxoethyl)azetidine-1-carboxylate (43 g, 157.3mmol) in ether (1 L) was added LAH (12 g, 316.2 mmol)) in severalportions, and the resultant mixture was stirred at rt overnight. Thereaction was quenched by the addition of satd. aq. NaHCO₃ (1.25 L) andthe mixture was extracted with EtOAc (3×500 mL). The combined extractswere dried (Na₂SO₄), filtered, and concentrated under reduced pressureto afford tert-butyl3-(2-hydroxyethyl)-3-sulfanylazetidine-1-carboxylate (23 g, 63%) as ared oil. ¹H NMR (CDCl₃) δ 4.07-4.10 (m, 2H), 3.86-3.95 (m, 4H), 2.21 (s,1H), 2.11 (t, J=6.3 Hz, 2H), 1.44 (s, 9H).

(D) To a cooled (−30° C.) solution of triphenylphosphine (80 g, 305.0mmol) in THF (1 L) under nitrogen was added DIAD (61.7 g, 305.1 mmol) indropwise fashion. After stirring at rt for 1 h, EtOH (28 g, 607.8 mmol)was added and stirring was continued at rt for 1 h. The mixture was thenconcentrated under reduced pressure and the mixture was diluted withhexane (1 L). The resulting precipitate was filtered, and the filtratewas concentrated under reduced pressure to provide diethyltriphenylphosphonite (76 g, 71%) as a colorless oil. ³¹P NMR (C₆D₆)6-41.6.

(E) To a cooled (−30° C.) solution of diethyl triphenylphosphonite (52g, 147.56 mmol) in toluene (250 mL) under a nitrogen atmosphere wasadded a solution of tert-butyl3-(2-hydroxyethyl)-3-sulfanylazetidine-1-carboxylate (23 g, 98.57 mmol)in toluene (250 mL) in drop-wise fashion, and the resultant solution wasstirred overnight at rt. EtOAc (500 mL) was then added and the solutionwas washed with brine (3×300 mL). The organic phase was then dried(Na₂SO₄), filtered, and concentrated under reduced pressure to affordtert-butyl 1-thia-6-azaspiro[3.3]heptane-6-carboxylate (8 g, 38%) as acolorless oil. ¹H NMR (CDCl₃) δ 4.07-4.16 (m, 4H), 3.05-3.15 (m, 4H),1.42-1.51 (m, 9H).

(F) To an ice-cooled solution of tert-butyl1-thia-6-azaspiro[3.3]heptane-6-carboxylate (8 g, 37.16 mmol) in DCM(250 mL) was added mCPBA (12.8 g, 74.17 mmol) and the resultant solutionwas stirred overnight at rt. DCM (200 mL) was then added and thesolution was successively extracted with 1N NaOH (3×150 mL) then withsatd. aq. NaHCO₃ (3×150 mL). The organic phase was dried (Na₂SO₄),filtered, concentrated under reduced pressure and the resultant residuewas purified by silica gel chromatography (9-33% EtOAc/petroleum ether)to afford tert-butyl 1-thia-6-azaspiro[3.3]heptane-6-carboxylate1,1-dioxide (4 g, 41%) as a white solid. ¹H NMR (CDCl₃) δ 4.57 (d,J=11.2 Hz, 2H), 4.00-4.06 (m, 4H), 2.37 (t, J=8.4 Hz, 2H), 1.14 (s, 9H).

(G) A solution of tert-butyl 1-thia-6-azaspiro[3.3]heptane-6-carboxylate1,1-dioxide (3.4 g, 13.75 mmol), DCM (8 mL) and TFA (4 mL) was stirredfor 2 h at rt, then concentrated under reduced pressure. The residue wastaken up in water (20 mL) and dried by lyophilization to afford the TFAsalt of 1-thia-6-azaspiro[3.3]heptane 1,1-dioxide (3.2 g, 86%) as awhite solid. ¹H NMR (DMSO-d₆) δ 4.30-4.40 (m, 4H), 4.06-4.12 (m, 2H),2.41-2.47 (m, 2H).

(H) Under an inert atmosphere of nitrogen, a mixture of1-thia-6-azaspiro[3.3]heptane 1,1-dioxide TFA (244 mg, 1 mmol),1-bromo-4-iodo-2-methylbenzene (385 mg, 1.30 mmol), Pd₂(dba)₃ (46 mg,0.05 mmol), CyJohnPhos (35 mg, 0.10 mmol) and t-BuONa (240 mg, 2.50mmol) in toluene (3 mL) was stirred at 50° C. overnight. Water (10 mL)was then added and the mixture was extracted with EtOAc (3×15 mL). Thecombined organic extracts were washed with brine (1×15 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure.Purification of the resultant residue by silica gel chromatography (40%EtOAc/petroleum ether) afforded6-(4-bromo-3-methylphenyl)-1-thia-6-azaspiro[3.3]heptane 1,1-dioxide(278 mg, 88%) as a yellow solid. LC/MS: mass calcd. for C₁₂H₁₄BrNO₂S:316.21, found: 316.1, 318.1 [M]⁺.

(I) Ethyl2-(3-oxo-1-(4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetatewas prepared from and ethyl2-(1-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetate(from Example 32C) and bis(pinacolato)diboron following GeneralProcedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc inplace of K₂CO₃ and DMSO as solvent at a reaction temperature of 100° C.overnight. LC/MS: mass calcd. for C₂₉H₃₃BO₆S: 520.44, found 543.4[M+Na]⁺.

(J) Ethyl2-(1-(4-((3-(4-(1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatewas prepared from ethyl2-(3-oxo-1-(4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetateand 6-(4-bromo-3-methylphenyl)-1-thia-6-azaspiro[3.3]heptane 1,1-dioxidefollowing General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst and DMF as solvent at a reaction temperature of 80° C.overnight. LC/MS: mass calcd. for C₃₅H₃₅NO₆S₂: 629.79, found: 630.4[M+H]⁺.

(K)2-(1-(4-((3-(4-(1,1-Dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid (Cpd 40) was prepared from ethyl2-(1-(4-((3-(4-(1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetatefollowing General Procedure C, using NaOH as base, MeCN in place of THFand 1N HCl for reaction acidification. Product purification wasaccomplished by silica gel chromatography (70% EtOAc/petroleum ether).¹H NMR (CD₃OD) δ 7.93-7.93 (m, 1H), 7.46-7.42 (m, 2H), 7.35 (s, 1H),7.29-7.27 (m, 2H), 7.18-7.11 (m, 1H), 6.98-6.93 (m, 2H), 6.54-6.49 (m,2H), 5.16 (s, 2H), 4.53 (d, J=9.6 Hz, 2H), 4.13-4.08 (m, 2H), 4.03 (d,J=9.6 Hz, 2H), 3.52-3.39 (m, 4H), 2.84 (s, 2H), 2.50-2.42 (m, 2H), 2.06(s, 3H). LC/MS: mass calcd. for C₃₃H_(3i)NO₆S₂: 601.73, found: 602.0[M]⁺.

Example 41(3S)-3-(4-((3-(2-Methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 41

(A)(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanolwas prepared from 3-bromo-5-hydroxymethylbenzothiophene (from Example1A) and bis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and KOAc in place of K₂CO₃.LC/MS: mass calcd. for C₁₅H₁₉BO₃S: 290.19, found: 273.1[M-OH]⁺.

(B)3-(2-Methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophene-5-carbaldehydewas prepared from(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanoland 2-bromo-4-methanesulfonyl-1-methylbenzene following GeneralProcedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, Cs₂CO₃in place of K₂CO₃. LC/MS: mass calcd. for C₁₇H₁₄O₃S₂: 330.42, found:331.0 [M+H]⁺.

(C) To an ice-cooled solution of3-(2-methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophene-5-carbaldehyde(120 mg, 0.36 mmol) in MeOH (2 mL) was added NaBH₄ (21 mg, 0.56 mmol).After stirring for 30 min at 0° C., the reaction was quenched by theaddition of satd. aq. NH₄Cl (5 mL) and the mixture was extracted withEtOAc (3×10 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (0-40% EtOAc/petroleum ether) toafford(3-(2-methyl-5-(methylsulfonyl)phenyl)benzo[b]-thiophen-5-yl)methanol asa light yellow oil (40 mg, 33%). LC/MS: mass calcd. for C₁₇H₁₆O₃S₂:332.44, found: 315.0 [M−OH]⁺.

(D) (3S)-Ethyl3-(4-((3-(2-methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(3-(2-methyl-5-(methylsulfonyl)phenyl)benzo[b]-thiophen-5-yl)methanoland (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure B, using Bu₃P and ADDP at a reactiontemperature of 60° C. for 1 h. LC/MS: mass calcd. for C₃₁H₃₀O₅S₂:546.70, found: 547.1 [M]⁺.

(E) (3S)-3-(4-((3-(2-Methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid(Cpd 41) was prepared from (3S)-ethyl3-(4-((3-(2-methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.12 (d, J=8.0Hz, 1H), 7.92 (dd, J=1.0, 8.0 Hz, 1H), 7.88 (s, 1H), 7.79-7.80 (m, 1H),7.67 (d, J=8.0 Hz, 1H), 7.52 (dd, J=1.2, 8.4 Hz, 1H), 7.43 (s, 1H), 7.24(d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.18 (s, 2H), 3.90-3.94 (m,1H), 3.26 (s, 3H), 2.54-2.58 (m, 2H), 2.17 (s, 3H), 1.76 (s, 3H). LC/MS:mass calcd. for C₂₉H₂₆O₅S₂: 518.64, found: 518.9 [M]⁺.

Example 42(3S)-3-(4-((3-(2-Methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 42

(A)3-(2-Methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophene-5-carbaldehydewas prepared from(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) and 1-bromo-4-methanesulfonyl-2-methylbenzenefollowing General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst, Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₁₇H₁₄O₃S₂:330.42, found: 331.1 [M+H]⁺.

(B) (3-(2-Methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methanolwas prepared from3-(2-methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophene-5-carbaldehydeand NaBH₄, following the procedure described in Example 41C. LC/MS: masscalcd. for C₁₇H₁₆O₃S₂: 332.44, found: 314.9 [M-OH]⁺.

(C) (3S)-Ethyl3-(4-((3-(2-methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(3-(2-methyl-5-(methylsulfonyl)phenyl)benzo[b]-thiophen-5-yl)methanoland (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure B, using Bu₃P and ADDP at a reactiontemperature of 60° C. overnight. LC/MS: mass calcd. for C₃₁H₃₀O₅S₂:546.70, found: 547.2 [M]⁺.

(D) (3S)-3-(4-((3-(2-Methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid(Cpd 42) was prepared from (3S)-ethyl 3-(4-((3-(2-methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 12.23 (br. s,1H), 8.11 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.85-7.87 (m, 2H), 7.51-7.57(m, 2H), 7.45 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H),5.17 (s, 2H), 3.90-3.95 (m, 1H), 3.29 (s, 3H), 2.54-2.59 (m, 2H), 2.21(s, 3H), 1.76 (s, 3H). LC/MS: mass calcd. for C₂₉H₂₆O₅S₂: 518.64, found:519.0 [M]⁺.

Example 43(3S)-3-(4-((3-(2-Methyl-5-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 43

(A) (3-(5-Amino-2-methylphenyl)benzo[b]thiophen-5-yl)methanol wasprepared from 3-bromo-4-methyl aniline and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₆H₁₅NOS: 269.36, found: 270.1 [M+H]⁺.

(B) (3S)-Ethyl3-(4-((3-(5-amino-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(3-(5-amino-2-methylphenyl)benzo[b]thiophen-5-yl)methanol and (3S)-ethyl3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator, Inc.,Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure B, using Bu₃P and ADDP at a reaction temperature of 60° C. for1 h. LC/MS: mass calcd. for C₃₀H₂₉NO₃S: 483.62, found: 484.0 [M]⁺.

(C) To an ice-cooled solution of (3S)-ethyl3-(4-((3-(5-amino-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(200 mg, 0.41 mmol) and pyridine (0.07 mL, 0.83 mmol) in DCM (2 mL) wasadded MSCl (0.05 mL, 0.62 mmol) and the resultant solution was stirredovernight at rt. Water (5 mL) was added and the mixture was extractedwith DCM (5 mL). The organic extracts were washed with 1N HCl (3×5 mL),dried (Na₂SO₄) and concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (0-20%EtOAc/petroleum ether) to afford (3S)-ethyl3-(4-((3-(2-methyl-5-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoateas a light yellow oil (200 mg, 78% yield). LC/MS: mass calcd. forC₃₁H₃₁NO₅S₂: 561.71, found: 562.1 [M]⁺.

(D)(3S)-3-(4-((3-(2-Methyl-5-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid was prepared from (3S)-ethyl3-(4-((3-(2-methyl-5-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.06 (d, J=8.4Hz, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.44-7.49 (m, 1H), 7.41 (d, J=8.4Hz, 1H), 7.23-7.30 (m, 3H), 7.17 (d, J=1.6 Hz, 1H), 6.92 (d, J=8.8 Hz,2H), 5.16 (s, 2H), 3.90-3.94 (m, 1H), 2.67 (s, 3H), 2.56-2.61 (m, 2H),2.34 (s, 3H), 1.79 (s, 3H). LC/MS: mass calcd. for C₂₉H₂₇NO₅S₂: 533.66,found: 550.9 [M+NH₃]⁺.

Example 44(3S)-3-(4-((3-(2-Methyl-6-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 44

(A) (3-(2-Amino-6-methylphenyl)benzo[b]thiophen-5-yl)methanol wasprepared from 2-bromo-3-methylaniline and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₆H₁₅NOS: 269.36, found: 270.1 [M+H]⁺.

(B) (3S)-Ethyl3-(4-((3-(2-amino-6-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(3-(2-amino-6-methylphenyl)benzo[b]thiophen-5-yl)methanol and (3S)-ethyl3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator, Inc.,Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure B, using Bu₃P and ADDP at a reaction temperature of 60° C. for1 h. LC/MS: mass calcd. for C₃₀H₂₉NO₃S: 483.62, found: 484.0 [M]⁺.

(C) (3S)-Ethyl 3-(4-((3-(2-methyl-6-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate wasprepared from (3S)-ethyl3-(4-((3-(2-amino-6-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoateand MsCl, following the procedure described in Example 43C. LC/MS: masscalcd. for C₃₁H₃₁NO₅S₂: 561.71, found: 562.1 [M]⁺.

(D)(3S)-3-(4-((3-(2-Methyl-6-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 44) was prepared from (3S)-ethyl3-(4-((3-(2-methyl-6-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 12.24 (br. s,1H), 8.46 (br. s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.47 (d,J=8.0 Hz, 1H), 7.37-7.39 (m, 2H), 7.21-7.23 (m, 4H), 6.89 (d, J=8.0 Hz,2H), 5.14 (s, 2H), 3.91-3.92 (m, 1H), 2.68 (s, 3H), 2.54-2.58 (m, 2H),1.88 (s, 3H), 1.79 (s, 3H). LC/MS: mass calcd. for C₂₉H₂₇NO₅S₂: 533.66,found: 551.0 [M+NH₃]⁺.

Example 453-(6-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid, Cpd 45

(A) A solution of 6-methoxypyridine-3-carbaldehyde (10 g, 73.00 mmol)and 2,2-dimethyl-1,3-dioxane-4,6-dione (11 g, 76.70 mmol) in water (150mL) was stirred for 2 h at 75° C., and then cooled in a water/ice bath.The resulting solids were collected by filtration and dried in an ovenunder reduced pressure to provide5-((6-methoxypyridin-3-yl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dioneas a yellow powder (18 g, 99%). LC/MS: mass calcd. for C₁₃H₁₃NO₅:263.25, found: 264.0 [M+H]⁺.

(B) To a solution of bromo(prop-1-yn-1-yl)magnesium (114 mL, 57.03 mmol,0.5 N in THF) in THF (300 mL) was added a solution of5-((6-methoxypyridin-3-yl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(10 g, 38.02 mmol) in THF (100 mL) in drop-wise fashion and theresulting solution was stirred at rt overnight. The reaction was thenquenched by the addition of of satd. aq. NH₄Cl (100 mL). The resultingmixture was extracted with 300 mL of hexane (which was discarded) andthe aqueous layer was collected. The pH of the aqueous layer wasadjusted to 2 with 1N HCl and the resulting solution was extracted withEtOAc (3×200 mL). The combined EtOAc extracts were dried (Na₂SO₄) andconcentrated under reduced pressure to provide5-(1-(6-methoxypyridin-3-yl)but-2-ynyl)-2,2-dimethyl-1,3-dioxane-4,6-dione(10 g, 87%) as a yellow solid. LC/MS: mass calcd. for C₁₆H₁₇NO₅: 303.31,found: 304.0 [M+H]⁺.

(C) A solution of5-(1-(6-methoxypyridin-3-yl)but-2-ynyl)-2,2-dimethyl-1,3-dioxane-4,6-dione(5 g, 16.48 mmol), DMF (100 mL) and water (10 mL) was stirred overnightat 100° C. The reaction was then quenched by the addition of satd. aq.NH₄Cl (200 mL) and the resulting mixture was extracted with EtOAc (3×200mL). The combined organic extracts were dried (Na₂SO₄) and concentratedunder reduced pressure to provide 3-(6-methoxypyridin-3-yl)hex-4-ynoicacid (3.5 g, 97%) as a red oil, which was used directly without furtherpurification. LC/MS: mass calcd. for C₁₂H₁₃NO₃: 219.24, found: 220.1[M+H]⁺.

(D) A solution of 3-(6-methoxypyridin-3-yl)hex-4-ynoic acid (8.8 g,40.18 mmol), dioxane (20 mL), water (20 mL) and conc. HCl (5 mL) wasstirred overnight at 100° C. After cooling to rt, the solution wasneutralized to pH 5 by the addition of satd. aq. NaHCO₃ and theresulting mixture was extracted with EtOAc (3×100 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated under reducedpressure to provide 3-(6-hydroxypyridin-3-yl)hex-4-ynoic acid (7.6 g,92%) as a brown oil, which was used directly without furtherpurification. LC/MS: mass calcd. for C₁₁H₁₁NO₃: 205.21, found: 206.0[M+H]⁺.

(E) A solution of 3-(6-hydroxypyridin-3-yl)hex-4-ynoic acid (8 g, 39.00mmol) in EtOH (45 mL) was treated with conc. H₂SO₄ (2 mL) and theresultant solution was stirred for 2 h at 80° C. After cooling to rt,the solution was neutralized to pH 5 by the addition of satd. aq. NaHCO₃and the resulting mixture was extracted with EtOAc (3×100 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (0-20% MeOH/DCM) to afford ethyl3-(6-hydroxypyridin-3-yl)hex-4-ynoate (2.2 g, 24.2%). ¹H NMR (CDCl₃) δ7.46-7.53 (m, 2H), 6.57 (d, J=9.3 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H),3.88-3.94 (m, 1H), 2.55-2.71 (m, 2H), 1.82 (d, J=2.4 Hz, 3H), 1.24 (t,J=7.2 Hz, 3H).

(F) To an ice-cooled solution of5-hydroxymethyl-3-(2-methylphenyl)benzo[b]-thiophene (from Example 1)(200 mg, 0.79 mmol) in DCM (10 mL) was added PBr₃ (640 mg, 2.36 mmol) indrop-wise fashion, followed by DMF (0.05 mL, cat.). After stirring at rtfor 1 h, water (10 mL) was added and the mixture was extracted with DCM(3×10 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure to afford5-(bromomethyl)-3-(2-methylphenyl)benzo[b]thiophene (150 mg, 60%) as ayellow oil, which was used directly in the following reaction.

(G) A mixture of 5-(bromomethyl)-3-(2-methylphenyl)benzo[b]thiophene(150 mg, 0.47 mmol), ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (220mg, 0.95 mmol) and Ag₂CO₃ (130 mg, 0.47 mmol) in toluene (5 mL) wasstirred for 2 h at 50° C. Water (20 mL) was then added and the mixturewas extracted with EtOAc (3×10 mL). The combined organic extracts weredried (Na₂SO₄), concentrated under reduced pressure and the residue thusobtained was purified by silica gel chromatography (0-5% EtOAc/petroleumether) to provide ethyl3-(6-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoate(90 mg, 41%) as a colorless oil. LC/MS: mass calcd. for C₂₉H₂₇NO₃S:469.59, found: 470.0 [M]⁺.

(H)3-(6-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 45) was prepared from ethyl3-(6-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 2N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.04-8.09 (m,2H), 6.69-7.71 (m, 2H), 7.48 (dd, J=1.2, 8.4 Hz, 1H), 7.22-7.42 (m, 5H),6.78 (d, J=8.8 Hz, 1H), 5.40 (s, 2H), 3.97-4.01 (m, 1H), 2.58-2.66 (m,2H), 2.07 (s, 3H), 1.77 (s, 3H). LC/MS: mass calcd. for C₂₇H₂₃NO₃S:441.54, found: 439.9 [M−H]⁻.

Example 463-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid, Cpd 46

(A) To a solution of(3-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methanol(240 mg, 0.68 mmol; from Example 15D) in DCM (20 mL) was added PBr₃(0.16 mL, 1.69 mmol) in drop-wise fashion. After stirring at rt for 1 h,satd. aq. NH₄Cl (30 mL) was added and the mixture was extracted with DCM(2×30 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The residue thus obtained waspurified by flash chromatography (0-15% EtOAc/petroleum ether) to afford4-(4-(5-(bromomethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)tetrahydro-2H-pyran(240 mg, 85%) as a colorless oil, which was used directly in thefollowing reaction.

(B) Ethyl3-(6-((3-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from4-(4-(5-(bromomethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)tetrahydro-2H-pyranand ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 45E)following the procedure described in Example 45G at a reactiontemperature of 60° C. overnight. LC/MS: mass calcd. for C₃₄H₃₅NO₅S:569.71, found: 570.4 [M+H]⁺.

(C)3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 46) was prepared from ethyl3-(6-((3-(2-methyl-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.09 (s, 1H),8.04 (d, J=8.4 Hz, 1H), 7.70 (dd, J=2.4, 8.4 Hz, 1H), 7.64 (s, 1H),7.43-7.48 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.91(dd, J=2.4, 8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 4.55-4.69(m, 1H), 3.96-4.04 (m, 1H), 3.85-3.89 (m, 2H), 3.54 (t, J=6.8 Hz, 2H),2.54-2.63 (m, 2H), 2.00-2.05 (m, 5H), 1.78 (d, J=2.4 Hz, 3H), 1.60-1.65(m, 2H). LC/MS: mass calcd. for C₃₂H₃₁NO₅S: 541.66, found: 542.2 [M]⁺.

Example 473-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid, Cpd 47

(A)5-(Bromomethyl)-3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophenewas prepared from[3-[4-(2-methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methanol(from Example 16D) and PBr3, following the procedure described inExample 46A, and used directly in the next step.

(B) Ethyl3-(6-((3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from5-(bromomethyl)-3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiopheneand ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 45E)following the procedure described in Example 45G at a reactiontemperature of 60° C. overnight. LC/MS: mass calcd. for C₃₂H₃₃NO₅S:543.67, found: 544.4 [M+H]⁺.

(C)3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 47) was prepared from ethyl3-(4-((3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 12.31 (br. s,1H), 8.10 (d, J=2.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.71 (dd, J=2.4,8.4 Hz, 1H), 7.64 (s, 1H), 7.42-7.48 (m, 2H), 7.16 (d, J=8.4 Hz, 1H),6.96 (d, J=2.4 Hz, 1H), 6.88 (dd, J=2.7, 8.4 Hz, 1H), 6.80 (d, J=8.4 Hz,1H), 5.40 (s, 2H), 4.14-4.17 (m, 2H), 3.96-4.02 (m, 1H), 3.68-3.71 (m,2H), 3.33 (s, 3H), 2.63-2.66 (m, 2H), 2.01 (s, 3H), 1.78 (s, 3H). LC/MS:mass calcd. for C₃₀H₂₉NO₅S: 515.62, found: 516.3 [M+H]⁺.

Example 48(3S)-3-(4-((3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 48

(A) A mixture of 6-bromo-5-methylpyridin-3-ol (1 g, 5.32 mmol),1-bromo-2-methoxyethane (730 mg, 5.25 mmol) and K₂CO₃ (1.5 g, 10.87mmol) in MeCN (20 mL) was stirred at rt overnight, after which thereaction was quenched by the addition of water (100 mL). The resultingsolution was extracted with EtOAc (2×100 mL) and the combined organicphase was dried (Na₂SO₄) and concentrated under reduced pressure. Theresultant residue was purified by silica gel chromatography (0-15%EtOAc/petroleum ether) to afford2-bromo-5-(2-methoxyethoxy)-3-methylpyridine (500 mg, 38%) as colorlessoil. LC/MS: mass calcd. for C₉H₁₂BrNO₂: 246.10, found: 246.0 [M]⁺, 248.0[M+2]⁺.

(B)(3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanolwas prepared from 2-bromo-5-(2-methoxyethoxy)-3-methylpyridine and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A, usingPdCl₂(dppf)CH₂Cl₂ as the palladium catalyst, Cs₂CO₃ in place of K₂CO₃.LC/MS: mass calcd. for C₁₈H₁₉NO₃S: 329.41, found: 330.0[M+H]⁺.

(C) (3S)-Ethyl3-(4-((3-(5-(2-methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(3-(5-(2-methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanoland (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure B, using Bu₃P and ADDP at a reactiontemperature of 50° C. in toluene for 2 h. LC/MS: mass calcd. forC₃₂H₃₃NO₅S: 543.67, found: 544.3 [M+H]⁺.

(D)(3S)-3-(4-((3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 48) was prepared from (3S)-ethyl3-(4-((3-(5-(2-methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 12.23 (br. s,1H), 8.27 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.69 (s, 1H),7.43-7.52 (m, 2H), 7.25 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 5.15(s, 2H), 4.23-4.28 (m, 2H), 3.91-3.96 (m, 1H), 3.72 (d, J=4.5 Hz, 2H),3.33 (s, 3H), 2.58 (d, J=7.5 Hz, 2H), 2.24 (s, 3H), 1.77 (d, J=2.4 Hz,3H). LC/MS: mass calcd. for C₃₀H₂₉NO₅S: 515.62, found: 516.2 [M+H]⁺.

Example 49(3S)-3-(4-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 49

(A) 3-Bromo-5-(2-methoxyethoxy)-2-methylpyridine was prepared from5-bromo-6-methylpyridin-3-ol and 1-bromo-2-methoxyethane following theprocedure described in Example 48A. LC/MS: mass calcd. for C₉H₁₂BrNO₂:246.10, found: 246.0[M]⁺, 248.0 [M+2]⁺.

(B)5-(2-Methoxyethoxy)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinewas prepared from 3-bromo-5-(2-methoxyethoxy)-2-methylpyridine andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ andDMSO as reaction solvent at a reaction temperature of 85° C. overnight.LC/MS: mass calcd. for C₁₅H₂₄BNO₄: 293.17, found: 294.1 [M+H]⁺.

(C) (3S)-Ethyl3-(4-((3-(5-(2-methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from5-(2-methoxyethoxy)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineand(3S)-ethyl-3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(from Example 11E) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₃₂H₃₃NO₅S: 543.67, found: 544.2 [M+H]⁺.

(D)(3S)-3-(4-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 49) was prepared from (3S)-ethyl3-(4-((3-(5-(2-methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.28 (d, J=3.0Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.48-7.52 (m, 2H), 7.30(d, J=2.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 5.18(s, 2H), 4.17-4.20 (m, 2H), 3.90-3.94 (m, 1H), 3.65-3.68 (m, 2H), 3.32(s, 3H), 2.54-2.57 (m, 2H), 2.20 (s, 3H), 1.76 (d, J=2.4 Hz, 3H). LC/MS:mass calcd. for C₃₀H₂₉NO₅S: 515.62, found: 516.2 [M+H]⁺.

Example 50(3S)-3-(4-((3-(6-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 50

(A) To a solution of 2-methoxyethan-1-ol (5.53 g, 72.8 mmol) inanhydrous THF (80 mL) was added NaH (60% wt in mineral oil; 2.91 g, 72.8mmol) in portions. After stirring at rt for 30 min, a solution of3-bromo-6-chloro-2-methylpyridine (5 g, 24.3 mmol) in THF (20 mL) wasadded in drop-wise fashion. Following the addition, the mixture wasstirred at 85° C. overnight. The reaction was then quenched by theaddition of satd. aq. NH₄Cl (100 mL) and the mixture was extracted withEtOAc (2×100 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel chromatography (0-10% EtOAc/petroleum ether) to afford3-bromo-6-(2-methoxyethoxy)-2-methylpyridine (5.6 g, 94% yield) as acolorless oil. LC/MS: mass calcd. for C₉H₁₂BrNO₂: 246.10, found: 246.0[M]⁺, 247.9 [M+2]⁺.

(B)6-(2-Methoxyethoxy)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinewas prepared from 3-bromo-6-(2-methoxyethoxy)-2-methylpyridine andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ andDMSO as reaction solvent at a reaction temperature of 85° C. overnight.LC/MS: mass calcd. for C₁₅H₂₄BNO₄: 293.17, found: 294.3 [M+H]⁺.

(C) (3S)-Ethyl3-(4-((3-(6-(2-methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from6-(2-methoxyethoxy)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineand (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) following General Procedure A, using PdCl₂(dppf).CH₂Cl₂ asthe palladium catalyst and Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd.for C₃₂H₃₃NO₅S: 543.67, found: 544.2 [M+H]⁺.

(D)(3S)-3-(4-((3-(6-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 50) was prepared from (3S)-ethyl3-(4-((3-(6-(2-methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.07 (d, J=8.1Hz, 1H), 7.68 (d, J=2.7 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.7Hz, 1H), 7.41 (s, 1H), 7.25 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H),6.80 (d, J=8.1 Hz, 1H), 5.19 (s, 2H), 4.42-4.44 (m, 2H), 3.86-3.94 (m,1H), 3.71-3.74 (m, 2H), 3.34 (s, 3H), 2.18 (s, 3H), 1.76 (d, J=2.1 Hz,3H). LC/MS: mass calcd. for C₃₀H₂₉NO₅S: 515.62, found: 516.2 [M+H]⁺.

Example 51(3S)-3-(4-((3-(6-(2-Methoxyethoxy)-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 51

(A) To a solution of 2-methoxyethan-1-ol (1.82 g, 24 mmol) in anhydrousTHF (20 mL) was added NaH (60% wt in mineral oil; 960 mg, 24 mmol) inportions. After stirring at rt for 30 min, the mixture was cooled to 0°C. and a solution of 2,5-dibromo-4-methylpyridine (2 g, 8 mmol) in THF(10 mL) was added in drop-wise fashion. The resultant mixture was thenheated at 80° C. overnight. The reaction was then quenched by theaddition of satd. aq. NH₄Cl (100 mL) and the mixture was extracted withEtOAc (2×100 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel chromatography (0-10% EtOAc/petroleum ether) to afford5-bromo-2-(2-methoxyethoxy)-4-methylpyridine (1.2 g, 61% yield) as alight yellow oil. LC/MS: mass calcd. for C₉H₁₂BrNO₂: 246.10, found:246.0 [M]⁺, 248.0 [M+2]⁺.

(B)2-(2-Methoxyethoxy)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinewas prepared from 5-bromo-2-(2-methoxyethoxy)-4-methylpyridine andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ andDMSO as reaction solvent at a reaction temperature of 85° C. overnight.LC/MS: mass calcd. for C₁₅H₂₄BNO₄: 293.17, found: 294.1 [M+H]⁺.

(C) (3S)-Ethyl3-(4-((3-(6-(2-methoxyethoxy)-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from2-(2-methoxyethoxy)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineand (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) following General Procedure A, using PdCl₂(dppf).CH₂Cl₂ asthe palladium catalyst and Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd.for C₃₂H₃₃NO₅S: 543.67, found: 544.2 [M+H]⁺.

(D)(3S)-3-(4-((3-(6-(2-Methoxyethoxy)-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid was prepared from (3S)-ethyl3-(4-((3-(6-(2-methoxyethoxy)-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 12.23 (br. s,1H), 8.08 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.50 (d, J=1.2Hz, 1H), 7.48 (s, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H),6.87 (s, 1H), 5.18 (s, 2H), 4.41-4.44 (m, 2H), 3.89-3.94 (m, 1H), 3.66(t, J=4.8 Hz, 2H), 3.33 (s, 3H), 2.58 (d, J=7.5 Hz, 2H), 2.04 (s, 3H),1.76 (d, J=2.4 Hz, 3H). LC/MS: mass calcd. for C₃₀H₂₉NO₅S: 515.62,found: 516.2 [M+H]⁺.

Example 52(3S)-3-(4-((3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 52

(A) (3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methanol wasprepared from 4-bromo-2-chloro-5-methylpyridine and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₅H₁₂ClNOS: 289.78, found: 290.0 [M]⁺,292.0 [M+2]⁺.

(B) (3S)-Ethyl3-(4-((3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from(3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methanol and(3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator,Inc., Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure B, using Bu₃P and ADDP at a reaction temperature of 60° C. intoluene overnight. LC/MS: mass calcd. for C₂₉H₂₆ClNO₃S: 504.04, found:504.1 [M]⁺, 506.1 [M+2]⁺.

(C)(3S)-3-(4-((3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 52) was prepared (3S)-ethyl3-(4-((3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using NaOH as base, MeOH as solvent and areaction temperature of 60° C. for 2 h. For workup, the reaction mixturewas filtered and concentrated, then purified directly by preparativeHPLC on a Waters SunFire™ Prep C18, 5μ column (19×100 mm) using anacetonitrile/water (0.5% NH₄HCO₃) gradient (65-75%). ¹H NMR (CD₃OD) δ8.31 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.49 (d, J=8.7 Hz,1H), 7.41 (s, 1H), 7.36 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4Hz, 2H), 5.16 (s, 2H), 3.90-3.98 (m, 1H), 2.48-2.63 (m, 2H), 2.05 (s,3H), 1.76 (s, 3H). LC/MS: mass calcd. for C₂₇H₂₂ClNO₃S: 475.99, found:476.1 [M]⁺, 478.1 [M+2]⁺.

Example 533-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)propanoicacid, Cpd 53

(A) A mixture of 4-bromobenzaldehyde (2 g, 10.81 mmol), ethylprop-2-enoate (1.62 g, 16.18 mmol), P(o-tol)₃ (327 mg, 1.08 mmol),Pd(OAc)₂ (120 mg, 0.53 mmol) and triethylamine (3.26 g, 32.22 mmol) inDMF (10 mL) was stirred overnight at 100° C. under an inert atmosphereof nitrogen in a sealed tube. After cooling to rt, satd. aq. NH₄Cl (100mL) was added and the mixture was extracted with EtOAc (3×100 mL). Thecombined organic extracts were washed with water (2×50 mL), concentratedunder reduced pressure, and the resultant residue was purified by silicagel chromatography (0-10% EtOAc/petroleum ether) to afford (E)-ethyl3-(4-formylphenyl)acrylate (2 g, 91%) as a yellow liquid. LC/MS: masscalcd. for C₁₂H₁₂O₃: 204.22, found: 205.1 [M+H]⁺.

(B) A mixture of (E)-ethyl 3-(4-formylphenyl)acrylate (2 g, 9.79 mmol),Pd/C (1 g, 10% wt) and ethanol (50 mL) was hydrogenated at 3.5 atm for 2h, then filtered. The filtrate was concentrated under reduced pressureand the resultant residue was purified by silica gel chromatography(0-15% EtOAc/petroleum ether) to provide ethyl3-(4-(hydroxymethyl)phenyl)propanoate (1.54 g, 76%) as a colorlessliquid. LC/MS: mass calcd. for C₁₂H₁₆O₃: 208.25, found: 191.0 [M-OH]⁺.

(C) Ethyl3-(4-((3-bromobenzo[b]thiophen-5-yloxy)methyl)phenyl)propanoate wasprepared from ethyl 3-(4-(hydroxymethyl)phenyl)propanoate and3-bromo-1-benzothiophen-5-ol (from Example 23C) following GeneralProcedure B using PBu₃ and ADDP in toluene as solvent (in place of THF)at a temperature of 60° C. overnight. ¹H NMR (DMSO-d₆) δ 7.95-8.00 (m,2H), 7.41 (d, J=8.1 Hz, 2H), 7.16-7.28 (m, 4H), 5.18 (s, 2H), 4.03 (dd,J=6.9, 14.1 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H),1.14 (t, J=7.5 Hz, 3H).

(D) Ethyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yloxy)methyl)phenyl)propanoatewas prepared from ethyl3-(4-((3-bromobenzo[b]thiophen-5-yloxy)methyl)phenyl) and2-methylphenylboronic acid following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₂₇H₂₆O₃S: 430.56, found: 431.3 [M+H]⁺.

(E)3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)propanoicacid (Cpd 53) was prepared from ethyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yloxy)methyl)phenyl)propanoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 7.94 (d, J=8.7 Hz, 1H), 7.65 (s, 1H),7.13-7.36 (m, 8H), 7.10 (d, J=2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 5.00(s, 2H), 2.79 (t, J=7.8 Hz, 2H), 2.42 (t, J=7.8 Hz, 2H), 2.05 (s, 3H).LC/MS: mass calcd. for C₂₅H₂₂O₃S: 402.51, found: 401.1 [M−H]⁻.

Example 54(3S)-3-[4-[([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid, Cpd 54

(A) Ethyl(3S)-3-[4-([[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]oxy]methyl)phenyl]hex-4-ynoatewas prepared from ethyl(3S)-3-(4-[[(3-bromo-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoate(from Example 23F) and (4-hydroxy-2-methylphenyl)boronic acid followingGeneral Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalystand Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₃₀H₂₈O₄S: 484.61,found: 485.3 [M+H]⁺.

(B) Ethyl(3S)-3-[4-[([3-[4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatewas prepared from ethyl(3S)-3-[4-([[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]oxy]methyl)phenyl]hex-4-ynoateand 3-methylbutane-1,3-diol following General Procedure B, using PBu₃(10% in hexane) and ADDP in toluene as solvent (in place of THF) at atemperature of 60° C. overnight. LC/MS: mass calcd. for C₃₅H₃₈O₅S:570.74, found: 571.5 [M+H]⁺.

(C)(3S)-3-[4-[([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid (Cpd 54) was prepared from ethyl(3S)-3-[4-[([3-[4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 2N HCl for reactionacidification. ¹H NMR (CD₃OD) δ 7.76-7.78 (m, 1H), 7.36-7.45 (m, 2H),7.27-7.36 (m, 3H), 7.04-7.15 (m, 2H), 6.79-6.94 (m, 3H), 5.03 (s, 2H),4.21 (t, J=6.8 Hz, 2H), 4.02-4.13 (m, 1H), 2.59-2.76 (m, 2H), 2.04 (t,J=6.8 Hz, 2H), 1.97 (s, 3H), 1.84 (d, J=2.4 Hz, 3H), 1.28 (s, 6H).LC/MS: mass calcd. for C₃₃H₃₄O₅S: 542.69, found: 541.2 [M−H]⁻.

Example 55(3S)-3-[4-[([3-[4-(2,3-Dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid, Cpd 55

(A) Ethyl(3S)-3-(4-[[(3-[4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2-methylphenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoatewas prepared from2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(from Example 13B) and (3S)-ethyl3-(4-(((3-bromobenzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoate(from Example 23F) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd for C₃₆H₃₈O₆S: 598.75, found 599.3 [M+H]⁺.

(B) A solution of ethyl(3S)-3-(4-[[(3-[4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2-methylphenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoate(200 mg, 0.33 mmol), THF (2 mL) and 2N HCl (2 mL, 2 mmol) was stirred atrt overnight. Water (20 mL) was then added and the mixture was extractedwith EtOAc (3×20 mL). The combined organic extracts were dried (Na₂SO₄),concentrated under reduced pressure and purified by silica gelchromatography [ethyl acetate/petroleum ether (0-50%)] to afford ethyl(3S)-3-[4-[([3-[4-(2,3-dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoate(60 mg, 19%) as light yellow oil. LC/MS: mass calcd for C₃₃H₃₄O₆S:558.68, found 559.2 [M+H]⁺.

(C)(3S)-3-[4-[([3-[4-(2,3-Dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid (Cpd 55) was prepared from ethyl(3S)-3-[4-[([3-[4-(2,3-dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 7.91 (d, J=8.8 Hz, 1H), 7.58 (s, 1H),7.32-7.37 (m, 4H), 7.09-7.11 (m, 2H), 6.92-6.93 (m, 1H), 6.81-6.87 (m,2H), 5.03 (s, 2H), 4.97-5.02 (m, 1H), 4.64-4.69 (m, 1H), 3.93-4.07 (m,2H), 3.89-3.92 (m, 1H), 3.81-3.85 (m, 1H), 3.47-3.48 (d, J=5.6 Hz, 2H),2.63 (d, J=5.6 Hz, 2H), 2.01 (s, 3H), 1.77 (s, 3H). LC/MS: mass calcdfor C₃₁H₃₀O₆S: 530.63, found 529.1 [M−H]⁻.

Example 56(3S)-3-(4-[[(3-[2-Methyl-4-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoicacid, Cpd 56

(A) Ethyl(3S)-3-(4-[[(3-[2-methyl-4-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoatewas prepared from4,4,5,5-tetramethyl-2-(2-methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)-1,3,2-dioxaborolane(from Example 14B) and ethyl(3S)-3-(4-[[(3-bromo-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoate(from Example 23F) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd for C₃₅H₃₆O₅S: 568.72, found 569.2 [M]⁺.

(B)(3S)-3-(4-[[(3-[2-Methyl-4-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoicacid (Cpd 56) was prepared from ethyl(3S)-3-(4-[[(3-[2-methyl-4-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 7.92 (d, J=8.7 Hz, 1H), 7.58 (s, 1H),7.32-7.38 (m, 4H), 7.06-7.18 (m, 2H), 6.99 (d, J=2.1 Hz, 2H), 6.88-6.92(m, 1H), 6.83 (d, J=2.4 Hz, 2H), 5.03 (s, 2H), 4.53 (d, J=5.7 Hz, 2H),4.34 (d, J=5.7 Hz, 2H), 4.11 (s, 2H), 3.95-4.05 (m, 1H), 2.60 (d, J=7.5Hz, 2H), 2.02 (s, 3H), 1.77 (d, J=2.4 Hz, 3H), 1.40 (s, 3H). LC/MS: masscalcd for C₃₃H₃₂O₅S: 540.67, found 541.2 [M+H]⁺, 558.2 [M+NH₃]⁺.

Example 57(3S)-3-[4-[([3-[2-Methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid, Cpd 57

(A) Ethyl(3S)-3-[4-[([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatewas prepared from4,4,5,5-tetramethyl-2-[2-methyl-4-(oxan-4-yloxy)phenyl]-1,3,2-dioxaborolane(from Example 15B) and ethyl(3S)-3-(4-[[(3-bromo-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoate(from Example 23F) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd for C₃₅H₃₆O₅S: 568.72, found 569.4 [M+H]⁺.

(B)(3S)-3-[4-[([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid (Cpd 57) was prepared from ethyl(3S)-3-[4-[([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. The residue thus obtained was partially purified bysilica gel chromatography [EtOAc/petroleum ether (50-75%). Furtherpurification was carried out by preparative HPLC on a Waters SunFire™Prep C18, 5μ column (19×100 mm) using an isocratic acetonitrile/water(0.05% TFA) eluent (71%). ¹H NMR (DMSO-d₆) δ 7.92 (d, J=8.7 Hz, 1H),7.59 (s, 1H), 7.35 (s, 4H), 7.17-7.04 (m, 2H), 7.00-6.86 (m, 2H), 6.82(d, J=2.4 Hz, 1H), 5.04 (s, 2H), 4.70-4.55 (m, 1H), 4.00-4.09 (m, 1H),3.89-3.92 (m, 2H), 3.52-3.59 (m, 2H), 2.64 (d, J=7.5 Hz, 2H), 1.96-2.04(m, 5H), 1.78 (s, 3H), 1.63-1.70 (m, 2H). LC/MS: mass calcd forC₃₃H₃₂O₅S: 540.67, found 539.1 [M−H]⁻.

Example 58(3S)-3-[4-[([3-[4-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid, Cpd 58

(A) Ethyl(3S)-3-[4-[([3-[4-(2-methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatewas prepared from2-(4-(2-methoxyethoxy)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(from Example 16B) and ethyl(3S)-3-(4-[[(3-bromo-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoate(from Example 23F) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd for C₃₃H₃₄O₅S: 542.69, found 543.2 [M+H]⁺.

(B)(3S)-3-[4-[([3-[4-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid (Cpd 58) was prepared from ethyl(3S)-3-[4-[([3-[4-(2-methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.27 (s, 1H), 7.92 (d, J=8.7 Hz, 1H),7.59 (s, 1H), 7.32-7.42 (m, 4H), 7.09-7.13 (m, 2H), 6.81-6.94 (m, 3H),5.03 (s, 2H), 4.14-4.17 (m, 2H), 3.92-4.01 (m, 1H), 3.68-3.71 (m, 2H),3.34 (s, 3H), 2.64 (d, J=7.5 Hz, 2H), 2.00 (s, 3H), 1.77 (s, 3H). LC/MS:mass calcd for C₃₁H₃₀O₅S: 514.63, found 513.0 [M−H]⁻.

Example 59(3S)-3-{4-[((3-{4-[(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)oxy)methyl]phenyl}hex-4-ynoicacid, Cpd 59

(A) (3S)-Ethyl3-(4-(((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatewas prepared from ethyl(3S)-3-[4-([[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]oxy]methyl)phenyl]hex-4-ynoate(from Example 54A) and (1,1-dioxotetrahydro-2H-thian-4-yl)methyl4-methylbenzene-1-sulfonate (from Example 17A) following the proceduredescribed in Example 17B at a reaction temperature of 60° C. LC/MS: masscalcd for C₃₆H₃₈O₆S₂: 630.81, found 631.5 [M+H]⁺.

(B)(3S)-3-{4-[((3-{4-[(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)oxy)methyl]phenyl}hex-4-ynoicacid (Cpd 59) was prepared from (3S)-ethyl3-(4-(((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 2N HCl for reactionacidification. ¹H NMR (CD₃OD) δ 7.74 (d, J=8.8 Hz, 1H), 7.21-7.37 (m,5H), 7.00-7.10 (m, 2H), 6.72-6.89 (m, 3H), 4.95 (s, 2H), 3.99-4.04 (m,1H), 3.92 (d, J=6.0 Hz, 2H), 2.99-3.23 (m, 4H), 2.62-2.65 (m, 2H),2.25-2.29 (m, 2H), 2.08-2.12 (m, 1H), 1.84-2.04 (m, 5H), 1.78 (d, J=2.4Hz, 3H). LC/MS: mass calcd. for C₃₄H₃₄O₆S₂: 602.76, found: 601.1 [M]⁻.

Example 60(3S)-3-(4-(((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid, Cpd 60

(A) (3S)-Ethyl3-(4-(((3-(2-methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatewas prepared from3-methyl-3-[3-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxymethyl]-thietane-1,1-dioxide(from Example 18C) and ethyl(3S)-3-(4-[[(3-bromo-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoate(from Example 23F) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd for C₃₅H₃₆O₆S₂: 616.79, found 617.4 [M+H]⁺.

(B)(3S)-3-(4-(((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid (Cpd 60) was prepared from (3S)-ethyl3-(4-(((3-(2-methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. Product purification was carried out by preparative HPLCon a Waters SunFire™ Prep C18, 5μ column (19×100 mm) using anacetonitrile/water (0.05% NH₄HCO₃) gradient (30-95%). ¹H NMR (DMSO-d₆) δ7.94 (d, J=8.8 Hz, 1H), 7.60 (s, 1H), 7.30-7.36 (m, 4H), 7.10-7.21 (m,2H), 6.99 (d, J=2.1 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.82 (d, J=2.4 Hz,1H), 5.04 (s, 2H), 4.21-4.26 (m, 2H), 4.14 (s, 2H), 3.97-4.09 (m, 3H),2.61 (d, J=7.2 Hz, 2H), 2.03 (s, 3H), 1.78 (s, 3H), 1.53 (s, 3H). LC/MS:mass calcd for C₃₃H₃₂O₆S₂: 588.73, found 587.1 [M−H]⁻.

Example 613-[6-([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoicacid, Cpd 61

(A) To a solution of (3-bromo-1-benzothiophen-5-yl)methanol (1.0 g, 4.11mmol) (from Example 1A) in DCM (20 mL) and DMF (1 mL) was addedphosphorous tribromide (1 mL, 10.6 mmol) in drop-wise fashion, and theresultant solution was stirred at rt for 1 h. Water (40 mL) was thenadded and the mixture was extracted with DCM (3×40 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated under reducedpressure to afford 3-bromo-5-(bromomethyl)-1-benzothiophene (1.1 g, 87%)as colorless oil, which was used directly without further purification.

(B) A mixture of 3-bromo-5-(bromomethyl)-1-benzothiophene (1.1 g, 3.59mmol), ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (880 mg, 3.77 mmol)(from Example 45E) and Ag₂CO₃ (0.79 g, 2.86 mmol) in toluene (30 mL) wasstirred at 60° C. overnight. The mixture was then concentrated underreduced pressure and the resultant residue was purified directly bysilica gel chromatography [EtOAc/petroleum ether (0-11%) to provideethyl3-[6-[(3-bromo-1-benzothiophen-5-yl)methoxy]pyridin-3-yl]hex-4-ynoate(950 mg, 58%) as light yellow oil. LC/MS: mass calcd for C₂₂H₂₀BrNO₃S:458.37, found 458.2 [M]⁺, 460.2 [M+2]⁺.

(C) Ethyl3-(6-[[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]methoxy]pyridin-3-yl)hex-4-ynoatewas prepared from ethyl3-[6-[(3-bromo-1-benzothiophen-5-yl)methoxy]pyridin-3-yl]hex-4-ynoateand (4-hydroxy-2-methylphenyl)boronic acid following General ProcedureA, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ inplace of K₂CO₃. LC/MS: mass calcd for C₂₉H₂₇NO₄S: 485.59, found 486.2[M+H]⁺.

(D) Ethyl3-[6-([3-[4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoatewas prepared from ethyl3-(6-[[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]methoxy]pyridin-3-yl)hex-4-ynoateand 3-methylbutane-1,3-diol following General Procedure B using PBu₃ andADDP with toluene as solvent and a reaction temperature of 60° C.overnight. LC/MS: mass calcd. for C₃₄H₃₇NO₅S: 571.73, found: 572.2[M+H]⁺.

(E)3-[6-([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoicacid (Cpd 61) was prepared from ethyl3-[6-([3-[4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. Product purification was carried out by preparative HPLCon a Waters SunFire™ Prep C18, 5μ column (19×100 mm) using anacetonitrile/water (0.05% NH₄HCO₃) gradient (35-75%). ¹H NMR (DMSO-d₆) δ8.10 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.70 (dd, J=8.4 Hz, 2.4Hz, 1H), 7.63 (s, 1H), 7.43-7.48 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.93(d, J=2.7 Hz, 1H), 6.84-6.88 (m, 1H), 6.79 (d, J=8.7 Hz, 1H), 5.40 (s,2H), 4.14 (t, J=6.9 Hz, 2H), 3.95-4.00 (m, 1H), 2.61-2.63 (m, 2H), 2.05(s, 3H), 1.88 (t, J=7.2 Hz, 2H), 1.77 (d, J=2.4 Hz, 3H), 1.19 (s, 6H).LC/MS: mass calcd for C₃₂H₃₃NO₅S: 543.67, found 544.3 [M+H]⁺.

Example 623-(6-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid, Cpd 62

(A) A mixture of ethyl3-(6-[[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]methoxy]pyridin-3-yl)hex-4-ynoate(200 mg, 0.41 mmol) (from Example 61C),(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzene-1-sulfonate (235mg, 0.82 mmol) and Cs₂CO₃ (269 mg, 0.83 mmol) in DMF (5 mL) was stirredat 80° C. overnight. Water (20 mL) was then added and the mixture wasextracted with EtOAc (3×20 mL). The combined organic extracts were dried(Na₂SO₄), concentrated under reduced pressure and purified by silica gelchromatography [ethyl acetate/petroleum ether (0-20%)] to afford ethyl3-[6-[(3-[4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2-methylphenyl]-1-benzothiophen-5-yl)methoxy]pyridin-3-yl]hex-4-ynoate(100 mg, 41%) as light yellow oil. LC/MS: mass calcd for C₃₅H₃₇NO₆S:599.74, found 600.4 [M+H]⁺.

(B) A mixture of ethyl3-[6-[(3-[4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-2-methylphenyl]-1-benzothiophen-5-yl)methoxy]pyridin-3-yl]hex-4-ynoate(100 mg, 0.17 mmol), THF (2 mL) and 2N aq. HCl (2 mL, 2 mmol) wasstirred at rt overnight. Water (10 mL) was then added and the mixturewas extracted with EtOAc (3×10 mL). The combined organic extracts weredried (Na₂SO₄), concentrated under reduced pressure and purified bysilica gel chromatography [ethyl acetate/petroleum ether (0-20%)] toafford ethyl3-[6-([3-[4-(2,3-dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoate(70 mg, 75%) as light yellow oil. LC/MS: mass calcd for C₃₂H₃₃NO₆S:559.67, found 560.3 [M+H]⁺.

(C)3-(6-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 62) was prepared from ethyl3-[6-([3-[4-(2,3-dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.08 (s, 1H), 8.02 (d, J=8.4 Hz, 1H),7.69 (dd, J=2.8, 8.8 Hz, 1H), 7.62 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.41(s, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.86 (dd,J=8.8, 2.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 5.40 (s, 2H), 4.05-4.08 (m,1H), 3.94-4.04 (m, 1H), 3.85-3.93 (m, 1H), 3.83-3.74 (m, 1H), 3.47 (d,J=5.6 Hz, 2H), 2.53-2.58 (m, 2H), 2.03 (s, 3H), 1.76 (s, 3H). LC/MS:mass calcd for C₃₀H₂₉NO₆S: 531.62, found 532.1 [M+H]⁺.

Example 633-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid, Cpd 63

(A) Ethyl3-(6-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from ethyl3-(6-[[3-(4-hydroxy-2-methylphenyl)-1-benzothiophen-5-yl]methoxy]pyridin-3-yl)hex-4-ynoate(from Example 61C) and (1,1-dioxotetrahydro-2H-thian-4-yl)methyl4-methylbenzene-1-sulfonate (from Example 17A) following the proceduredescribed for Example 17B, at a reaction temperature of 60° C. LC/MS:mass calcd for C₃₅H₃₇NO₆S₂: 631.80, found 632.3 [M+H]⁺.

(B)3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 63) was prepared from ethyl3-(6-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.25-12.40 (m, 1H), 8.10 (s, 1H),8.04 (d, J=8.4 Hz, 1H), 7.71 (dd, J=2.4, 8.4 Hz, 1H), 7.64 (s, 1H),7.43-7.51 (m, 3H), 7.17 (d, J=8.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.89(dd, J=2.4, 8.4 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 5.40 (s, 2H), 3.95-4.00(m, 3H), 3.19-3.33 (m, 2H), 3.08-3.12 (m, 2H), 2.59-2.69 (m, 2H),2.16-2.20 (m, 3H), 2.06 (s, 3H), 1.78-1.85 (m, 5H). LC/MS: mass calcdfor C₃₃H₃₃NO₆S₂: 603.75, found 604.4 [M+H]⁺.

Example 643-(6-((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid, Cpd 64

(A) Ethyl3-(6-((3-(2-methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from ethyl3-[6-[(3-bromo-1-benzothiophen-5-yl)methoxy]pyridin-3-yl]hex-4-ynoate(from Example 61B) and3-methyl-3-[3-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxymethyl]-thietane-1,1-dioxide(from Example 18C) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd for C₃₄H₃₅NO₆S₂: 617.77, found 618.2 [M+H]⁺.

(B)3-(6-((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid, (Cpd 64) was prepared from ethyl3-(6-((3-(2-methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. Product purification was carried out by preparative HPLCon a Waters SunFire™ Prep C18, 5μ column (19×100 mm) using anacetonitrile/water (0.05% NH₄HCO₃) gradient (35-65%). ¹H NMR (DMSO-d₆) δ8.10 (d, J=2.4 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.71 (dd, J=8.7, 2.4 Hz,1H), 7.64 (s, 1H), 7.47 (dd, J=8.4, 1.5 Hz, 1H), 7.42 (s, 1H), 7.19 (d,J=8.4 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H),6.79 (d, J=8.4 Hz, 1H), 5.39 (s, 2H), 4.17-4.26 (m, 2H), 4.12 (s, 2H),3.93-4.06 (m, 3H), 2.51-2.73 (m, 2H), 2.06 (s, 3H), 1.77 (s, 3H), 1.52(s, 3H). LC/MS: mass calcd for C₃₂H₃₁NO₆S₂: 589.72, found 588.1 [M−H]⁻.

Example 65(3S)-3-[4-([3-[5-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid, Cpd 65

(A) 2-Bromo-4-(2-methoxyethoxy)-1-methylbenzene was prepared from3-bromo-4-methylphenol and 1-bromo-2-methoxyethane following theprocedure described in Example 16A. GC/MS: mass calcd. for C₁₀H₁₃BrO₂:244.01, found: 244.1 [M]⁺, 246.1 [M+2]⁺.

(B)2-[5-(2-Methoxyethoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared from 2-bromo-4-(2-methoxyethoxy)-1-methylbenzene andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ andDMSO as solvent. ¹H NMR (CDCl₃) δ 7.31-7.32 (m, 1H), 7.05-7.10 (m, 1H),6.88-6.93 (m, 1H), 4.11-4.14 (m, 2H), 3.72-3.75 (m, 2H), 3.44 (s, 3H),2.46 (s, 3H), 1.33 (s, 12H).

(C) Ethyl(3S)-3-[4-([3-[5-(2-methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoatewas prepared from ethyl(3S)-3-[4-[(3-bromo-1-benzothiophen-5-yl)methoxy]phenyl]hex-4-ynoate(from Example 11E) and2-[5-(2-methoxyethoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefollowing General Procedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladiumcatalyst and Cs₂CO₃ in place of K₂CO₃. ¹H NMR (CDCl₃) δ 7.80-7.90 (m,1H), 7.45-7.58 (m, 2H), 7.30-7.35 (m, 2H), 7.13-7.20 (m, 2H), 6.86-6.90(m, 4H), 5.08 (s, 2H), 4.05-4.13 (m, 4H), 3.73-3.76 (m, 2H), 3.44 (s,3H), 2.63-2.71 (m, 2H), 2.06 (s, 3H), 1.81 (s, 3H), 1.15-1.25 (m, 3H).

(D)(3S)-3-[4-([3-[5-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid (Cpd 65) was prepared from ethyl(3S)-3-[4-([3-[5-(2-methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a reaction temperature of 30° C. overnight and 1N HCl for reactionacidification. Additional product purification was carried out by silicagel chromatography [EtOAc/petroleum ether (1:1)]. ¹H NMR (DMSO-d₆) δ8.07 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.45-7.49 (m, 2H), 7.23-7.28 (m,3H), 6.90-6.96 (m, 3H), 6.82 (d, J=2.8 Hz, 1H), 5.18 (s, 2H), 4.07-4.09(m, 2H), 3.90-3.94 (m, 1H), 3.64 (t, J=4.4 Hz, 2H), 3.29 (s, 3H), 2.56(d, J=8.4 Hz, 2H), 1.99 (s, 3H), 1.76 (s, 3H). LC/MS: mass calcd forC₃₁H₃₀O₅S: 514.63, found 515.2 [M+H]⁺, 537.2 [M+Na]⁺.

Example 66(3S)-3-[4-([3-[2-(2-Methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid, Cpd 66

(A) 2-Bromo-3-(2-methoxyethoxy)-1-methylbenzene was prepared from2-bromo-3-methylphenol and 1-bromo-2-methoxyethane following theprocedure described in Example 16A. GC/MS: mass calcd. for C₁₀H_(n)BrO₂:244.01, found: 244.1 [M]⁺, 246.1 [M+2]⁺.

(B)[3-[2-(2-Methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methanolwas prepared from 2-bromo-3-(2-methoxyethoxy)-1-methylbenzene and[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-5-yl]methanol(from Example 41A) following General Procedure A, using Pd(OAc)₂ as thepalladium catalyst, P(o-Tol)₃ as an additional ligand (0.1 eq) and DMEas solvent at 100° C. overnight. ¹H NMR (DMSO-d₆) δ 7.93 (d, J=8.0 Hz,1H), 7.53 (s, 1H), 7.28-7.32 (m, 2H), 7.17 (s, 1H), 6.98 (t, J=7.6 Hz,2H), 5.15-5.17 (m, 1H), 4.54 (d, J=4.4 Hz, 2H), 3.95-4.05 (m, 2H),3.28-3.39 (m, 2H), 2.96 (s, 3H), 1.99 (s, 3H).

(C) Ethyl(3S)-3-[4-([3-[2-(2-methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoatewas prepared from[3-[2-(2-methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methanoland (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure B, using Bu₃P and ADDP at a reactiontemperature of 60° C. overnight. LC/MS: mass calcd. for C₃₃H₃₄O₅S:542.69, found: 543.2 [M+H]⁺.

(D)(3S)-3-[4-([3-[2-(2-Methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid (Cpd 66) was prepared from ethyl(3S)-3-[4-([3-[2-(2-methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a reaction temperature of 30° C. overnight and satd. aq. NH₄Cl forreaction acidification. Following an extractive workup (EtOAc), productpurification was carried out by silica gel chromatography [DCM/MeOH(11:1)]. ¹H NMR (DMSO-d₆) δ 8.01 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.45(dd, J=1.2, 8.4 Hz, 1H), 7.22-7.32 (m, 4H), 6.89-6.99 (m, 4H), 5.13 (s,2H), 3.89-4.01 (m, 3H), 3.22-3.28 (m, 2H), 3.22 (s, 3H), 2.57 (d, J=8.0Hz, 2H), 1.98 (s, 3H), 1.76 (s, 3H). LC/MS: mass calcd. for C₃₁H₃₀O₅S:514.63, found: 515.2 [M+H]⁺, 537.2 [M+Na]⁺.

Example 67(3S)-3-[4-([3-[3-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid, Cpd 67

(A) 1-Bromo-3-(2-methoxyethoxy)-2-methylbenzene was prepared from3-bromo-2-methylphenol and 1-bromo-2-methoxyethane following theprocedure described in Example 16A. GC/MS: mass calcd. for C₁₀H₁₃BrO₂:244.01, found: 244.0 [M]⁺, 246.0 [M+2]⁺.

(B)2-[3-(2-Methoxyethoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared from 1-bromo-3-(2-methoxyethoxy)-2-methylbenzene andbis(pinacolato)diboron following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, KOAc in place of K₂CO₃ andDMSO as solvent at a reaction temperature of 90° C. overnight. ¹H NMR(CDCl₃) δ 7.35 (dd, J=7.5, 1.2 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H),6.91-6.93 (m, 1H), 4.09-4.12 (m, 2H), 3.75-3.78 (m, 2H), 3.46 (s, 3H),2.44 (s, 3H), 1.34 (s, 12H).

(C) Ethyl(3S)-3-[4-([3-[3-(methoxymethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoatewas prepared from2-[3-(2-methoxyethoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand ethyl(3S)-3-[4-[(3-bromo-1-benzothiophen-5-yl)methoxy]phenyl]hex-4-ynoate(from Example 11E) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₃₃H₃₄O₅S: 542.69, found: 543.2 [M+H]⁺.

(D)(3S)-3-[4-([3-[3-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid (Cpd 67) was prepared from ethyl(3S)-3-[4-([3-[3-(methoxymethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place of MeOHand 1N HCl for reaction acidification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.06(d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.39-7.40 (m,1H), 7.21-7.28 (m, 3H), 7.04-7.07 (m, 1H), 6.85-6.90 (m, 3H), 5.15 (s,2H), 4.15-4.18 (m, 2H), 3.89-3.95 (m, 1H), 3.71-3.74 (m, 2H), 3.35 (s,3H), 2.36-2.44 (m, 2H), 1.92 (s, 3H), 1.75 (s, 3H). LC/MS: mass calcd.for C₃₁H₃₀O₅S: 514.63, found: 515.2 [M+H]⁺, 537.2 [M+Na]⁺.

Example 68(3S)-3-[4-([3-[2-(2-Methoxyethoxy)phenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid, Cpd 68

(A) Ethyl(3S)-3-[4-([[3-(2-hydroxyphenyl)-1-benzothiophen-5-yl]oxy]methyl)phenyl]hex-4-ynoatewas prepared from ethyl(3S)-3-[4-[(3-bromo-1-benzothiophen-5-yl)methoxy]phenyl]hex-4-ynoate(from Example 11E) and (2-hydroxyphenyl)boronic acid following GeneralProcedure A, using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst, Cs₂CO₃in place of K₂CO₃ and a reaction temperature of 80° C. overnight. ¹H NMR(CDCl₃) δ 7.93 (d, J=3.3 Hz, 1H), 7.65 (s, 1H), 7.48-7.52 (m, 2H),7.29-7.37 (m, 4H), 7.01-7.07 (m, 2H), 6.90 (dd, J=1.8, 6.6 Hz, 2H), 5.12(s, 2H), 4.04-4.13 (m, 3H), 2.64-2.72 (m, 2H), 1.83 (s, 3H), 1.19-1.28(m, 3H).

(B) Ethyl(3S)-3-[4-[([3-[2-(2-methoxyethoxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatewas prepared from ethyl(3S)-3-[4-([[3-(2-hydroxyphenyl)-1-benzothiophen-5-yl]oxy]methyl)phenyl]hex-4-ynoateand 1-bromo-2-methoxyethane following the procedure described in Example16A. LC/MS: mass calcd. for C₃₂H₃₂O₅S: 528.66, found: 546.2 [M+NH₃]⁺.

(C)(3S)-3-[4-([3-[2-(2-Methoxyethoxy)phenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid (Cpd 68) was prepared from ethyl(3S)-3-[4-[([3-[2-(2-methoxyethoxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a reaction temperature of 30° C. overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.02 (d, J=8.4 Hz, 1H), 7.72 (s, 1H),7.62 (s, 1H), 7.34-7.47 (m, 3H), 7.18-7.26 (m, 3H), 7.05-7.09 (m, 1H),6.92 (d, J=8.8 Hz, 2H), 5.16 (s, 2H), 4.09 (t, J=4.8 Hz, 2H), 3.91-3.93(m, 1H), 3.44 (t, J=8.4 Hz, 2H), 3.04 (s, 3H), 2.49-2.51 (m, 2H), 1.76(s, 3H). LC/MS: mass calcd. for C₃₀H₂₈O₅S: 500.61, found: 501.2 [M+H]⁺.

Example 69(3S)-3-(4-[[3-(2-Methanesulfonylphenyl)-1-benzothiophen-6-yl]methoxy]phenyl)hex-4-ynoicacid, Cpd 69

(A) [3-(2-Methanesulfonylphenyl)-1-benzothiophen-5-yl]methanol wasprepared from(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) and 1-bromo-2-methanesulfonylbenzene followingGeneral Procedure A, using Pd(OAc)₂ as the palladium catalyst, P(o-Tol)₃as an additional ligand (0.1 eq) and DME as solvent at 100° C. for 2 h.LC/MS: mass calcd. for C₁₆H₁₄O₃S₂: 318.41, found: 301.0 [M−OH]⁺.

(B) Ethyl(3S)-3-(4-[[3-(2-methanesulfonylphenyl)-1-benzothiophen-5-yl]methoxy]phenyl)hex-4-ynoatewas prepared from[3-(2-methanesulfonylphenyl)-1-benzothiophen-5-yl]methanol and(3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator,Inc., Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure B, using Bu₃P, ADDP and toluene as solvent (in place of THF)at a reaction temperature of 50° C. for 2 h. LC/MS: mass calcd. forC₃₀H₂₈O₅S₂: 532.67, found: 533.2 [M+H]⁺, 555.2 [M+Na]⁺.

(C)(3S)-3-(4-[[3-(2-Methanesulfonylphenyl)-1-benzothiophen-6-yl]methoxy]phenyl)hex-4-ynoicacid (Cpd 69) was prepared from ethyl(3S)-3-(4-[[3-(2-methanesulfonylphenyl)-1-benzothiophen-5-yl]methoxy]phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (CD₃OD) δ 8.24 (d, J=1.2 Hz, 1H), 8.00 (d, J=8.1Hz, 1H), 7.70-7.84 (m, 3H), 7.46-7.52 (m, 2H), 7.38 (s, 1H), 7.24 (d,J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.15 (s, 2H), 3.96-3.98 (m, 1H),2.57-2.68 (m, 5H), 1.80 (d, J=2.4 Hz, 3H). LC/MS: mass calcd. forC₂₈H₂₄O₅S₂: 504.62, found: 505.1 [M+H]⁺.

Examples 70 and 71(3S)-3-(6-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 70) and(3R)-3-(6-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 71)

(A) Enantiomeric resolution of(3RS)-3-(6-((3-(4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 61) was carried out by chiral chromatography on a ChiralPakAS-H 5μ column (2×25 cm) using an isocratic mobile phase [hexane (0.1%HOAc)/EtOH (85:15); 20 mL/min] to afford(3S)-3-(6-((3-(4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 70) (RT=9.0 min) and(3R)-3-(6-((3-(4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 71) (RT=12.5 min).

(Cpd 70): ¹H NMR (DMSO-d₆) δ 8.10 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.1 Hz,1H), 7.70 (dd, J=8.4, 2.4 Hz, 1H), 7.63 (s, 1H), 7.43-7.48 (m, 2H), 7.15(d, J=8.4 Hz, 1H), 6.94 (d, J=2.7 Hz, 1H), 6.85-6.88 (m, 1H), 6.79 (d,J=8.7 Hz, 1H), 5.40 (s, 2H), 4.14 (t, J=6.9 Hz, 2H), 3.95-4.05 (m, 1H),2.61-2.73 (m, 2H), 2.05 (s, 3H), 1.88 (t, J=7.2 Hz, 2H), 1.77 (d, J=2.4Hz, 3H), 1.19 (s, 6H). LC/MS: mass calcd. for C₃₄H₃₇NO₅S: 571.73, found:572.2 [M+H]⁺. LC/MS: mass calcd. for C₃₂H₃₃NO₅S: 543.67, found: 541.9[M−H]⁻.

(Cpd 71): ¹H NMR (DMSO-d₆) δ 8.10 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.1 Hz,1H), 7.70 (dd, J=8.4, 2.4 Hz, 1H), 7.63 (s, 1H), 7.43-7.48 (m, 2H), 7.15(d, J=8.4 Hz, 1H), 6.94 (d, J=2.7 Hz, 1H), 6.85-6.88 (m, 1H), 6.79 (d,J=8.7 Hz, 1H), 5.40 (s, 2H), 4.14 (t, J=6.9 Hz, 2H), 3.95-4.05 (m, 1H),2.61-2.73 (m, 2H), 2.05 (s, 3H), 1.88 (t, J=7.2 Hz, 2H), 1.77 (d, J=2.4Hz, 3H), 1.19 (s, 6H). LC/MS: mass calcd. for C₃₄H₃₇NO₅S: 571.73, found:572.2 [M+H]⁺. LC/MS: mass calcd. for C₃₂H₃₃NO₅S: 543.67, found: 542.1[M−H]⁻.

Examples 72 and 73(3S)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 72) and(3R)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 73)

(A) [3-[2-Methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methanolwas prepared from (3-bromo-1-benzothiophen-5-yl)methanol (from Example1A) and4,4,5,5-tetramethyl-2-[2-methyl-4-(oxan-4-yloxy)phenyl]-1,3,2-dioxaborolane(from Example 15B) following General Procedure A, usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd for C₂₁H₂₂O₃S: 354.46, found 337.2 [M-OH]⁺.

-   -   (B) To a solution of        [3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methanol        (240 mg, 0.68 mmol) in DCM (20 mL) was added PBr3 (0.16 mL, 1.7        mmol) in dropwise fashion. After stirring at rt for 1 h, the        reaction was quenched by the addition of NH₄Cl (30 mL) and the        mixture was extracted with EtOAc (2×30 mL), dried (Na₂SO₄) and        concentrated under reduced pressure. The resultant residue was        purified by silica gel chromatography (11% EtOAc/hexane) to        afford        4-[4-[5-(bromomethyl)-1-benzothiophen-3-yl]-3-methylphenoxy]oxane        (140 mg, 50%) as colorless oil, which was used directly without        characterization.

(C) A mixture of4-[4-[5-(bromomethyl)-1-benzothiophen-3-yl]-3-methylphenoxy]oxane (240mg, 0.58 mmol), ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (237 mg,1.02 mmol) (from Example 45E) and Ag₂CO₃ (150 mg, 0.54 mmol) in toluene(8 mL) was stirred at 60° C. overnight. The the reaction was quenched bythe addition of NH₄Cl (10 mL) and the mixture was extracted with EtOAc(3×10 mL), dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the resultant residue by silica gel chromatography[EtOAc/petroleum ether (14%) afforded ethyl3-[6-([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoate(80 mg, 24%) as colorless oil. LC/MS: mass calcd for C₃₄H₃₅NO₅S: 569.71,found 570.4 [M+H]⁺.

-   -   (D)        3-[6-([3-[2-Methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoic        acid was prepared from ethyl        3-[6-([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoate        following General Procedure C, using LiOH as base, EtOH in place        of MeOH, a rt reaction temperature overnight and 1N HCl for        reaction acidification. The product precipitated directly upon        acidification and was isolated by filtration. LC/MS: mass calcd        for C₃₂H₃₁NO₅S: 541.66, found 542.2 [M+H]⁺.

(E) Enantiomeric resolution of3-[6-([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoicacid was carried out by chiral chromatography on a ChiralPak AS-H 5μcolumn (2×25 cm) using an isocratic mobile phase [hexane (0.1%HOAc)/EtOH (70:30); 20 mL/min] to afford(3S)-3-[6-([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoicacid (Cpd 72) (RT=6 min) and(3R)-3-[6-([3-[2-methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoicacid (Cpd 73) (RT=9 min).

(Cpd 72): ¹H NMR (DMSO-d₆) δ 12.20-12.60 (br. m, 1H), 8.09 (s, 1H), 8.03(d, J=8.4 Hz, 1H), 7.71 (dd, J=8.4, 2.4 Hz, 1H), 7.64 (s, 1H), 7.43-7.48(m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.92 (dd,J=8.4, 2.7 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 5.41 (s, 2H), 4.55-4.65 (m,1H), 3.95-4.04 (m, 1H), 3.85-3.89 (m, 2H), 3.48-3.54 (m, 2H), 2.60 (t,J=6.8 Hz, 2H), 1.95-2.05 (m, 5H), 1.77 (d, J=2.4 Hz, 3H), 1.55-1.65 (m,2H). LC/MS: mass calcd. for C₃₂H₃₁NO₅S: 541.66, found: 542.1 [M+H]⁺.

(Cpd 73): ¹H NMR (DMSO-d₆) δ 12.20-12.60 (br. m, 1H), 8.09 (s, 1H), 8.03(d, J=8.4 Hz, 1H), 7.71 (dd, J=8.4, 2.4 Hz, 1H), 7.64 (s, 1H), 7.43-7.48(m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.92 (dd,J=8.4, 2.7 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 5.41 (s, 2H), 4.55-4.65 (m,1H), 3.95-4.04 (m, 1H), 3.85-3.89 (m, 2H), 3.48-3.54 (m, 2H), 2.60 (t,J=6.8 Hz, 2H), 1.95-2.05 (m, 5H), 1.77 (d, J=2.4 Hz, 3H), 1.55-1.65 (m,2H). LC/MS: mass calcd. for C₃₂H₃₁NO₅S: 541.66, found: 540.1 [M−H]⁻.

Examples 74 and 75(3S)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid (Cpd 74) and(3R)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid (Cpd 75)

Enantiomeric resolution of3-(6-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid (Cpd 63) was carried out by chiral chromatography on aChiralPak AS-H 5μ column (2×25 cm) using an isocratic mobile phase[hexane (0.1% HOAc)/EtOH (50:50); 18 mL/min] to afford(3S)-3-(6-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid (Cpd 74) (RT=16 min) and(3R)-3-(6-((3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 75) (RT=22 min).

(Cpd 74): ¹H NMR (DMSO-d₆) δ 8.10 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.71(dd, J=2.4, 8.4 Hz, 1H), 7.64 (s, 1H), 7.43-7.51 (m, 2H), 7.17 (d, J=8.4Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.89 (dd, J=2.7, 8.4 Hz, 1H), 6.80 (d,J=8.8 Hz, 1H), 5.40 (s, 2H), 3.95-4.00 (m, 3H), 3.19-3.33 (m, 2H),3.08-3.12 (m, 2H), 2.59-2.69 (m, 2H), 2.16-2.20 (m, 3H), 2.06 (s, 3H),1.78-1.85 (m, 5H). LC/MS: mass calcd. for C₃₃H₃₃NO₆S₂: 603.75, found:604.1 [M+H]⁺.

(Cpd 75): ¹H NMR (DMSO-d₆) δ 8.10 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.71(dd, J=2.4, 8.4 Hz, 1H), 7.64 (s, 1H), 7.43-7.51 (m, 2H), 7.17 (d, J=8.4Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.89 (dd, J=2.7, 8.4 Hz, 1H), 6.80 (d,J=8.8 Hz, 1H), 5.39 (s, 2H), 3.95-4.00 (m, 3H), 3.05-3.33 (m, 4H),2.59-2.69 (m, 2H), 2.16-2.20 (m, 3H), 2.06 (s, 3H), 1.78-1.85 (m, 5H).LC/MS: mass calcd. for C₃₃H₃₃NO₆S₂: 603.75, found: 604.1 [M+H]⁺.

Examples 76 and 77(3S)-3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 76) and(3R)-3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 77)

Enantiomeric resolution of3-(6-((3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]-thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 47) was carried out by chiral chromatography on a ChiralPakAS-H 5μ column (2×25 cm) using an isocratic mobile phase [hexane (0.1%HOAc)/EtOH (85:15); 20 mL/min] to afford(3S)-3-(6-((3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 76) (RT=8 min) and(3R)-3-(6-((3-(4-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 77) (RT=13.5 min).

(Cpd 76): ¹H NMR (DMSO-d₆) δ 8.10 (d, J=2.4 Hz, 1H), 8.04 (d, J=8.4 Hz,1H), 7.71 (dd, J=2.4, 8.4 Hz, 1H), 7.64 (s, 1H), 7.42-7.48 (m, 2H), 7.16(d, J=8.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H),6.80 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 4.14-4.17 (m, 2H), 3.96-4.02 (m,2H), 3.68-3.71 (m, 2H), 3.33 (d, J=6.0 Hz, 3H), 2.64 (dd, J=2.1, 7.8 Hz,2H), 2.01 (s, 3H), 1.77 (d, J=2.4 Hz, 3H). LC/MS: mass calcd. forC₃₀H₂₉NO₅S: 515.62, found: 514.1 [M−H]⁻.

(Cpd 77): ¹H NMR (DMSO-d₆) δ 8.10 (d, J=2.4 Hz, 1H), 8.04 (d, J=8.4 Hz,1H), 7.71 (dd, J=2.4, 8.4 Hz, 1H), 7.64 (s, 1H), 7.42-7.48 (m, 2H), 7.16(d, J=8.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H),6.80 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 4.14-4.17 (m, 2H), 3.96-4.02 (m,2H), 3.68-3.71 (m, 2H), 3.33 (d, J=6.0 Hz, 3H), 2.64 (dd, J=2.1, 7.8 Hz,2H), 2.01 (s, 3H), 1.77 (d, J=2.4 Hz, 3H). LC/MS: mass calcd. forC₃₀H₂₉NO₅S: 515.62, found: 514.1 [M−H]⁻.

Example 78(3S)-3-(4-((3-(2-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 78)

(A) (3S)-Ethyl3-(4-((3-(2-methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and 2-methoxypyridin-3-ylboronic acid following GeneralProcedure A using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst andCs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₂₉H₂₇NO₄S: 485.59,found: 486.2 [M+H]⁺.

(B)(3S)-3-(4-((3-(2-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 78) was prepared from (3S)-ethyl3-(4-((3-(2-methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.22 (br. s, 1H), 8.27-8.29 (m, 1H),8.06 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.77-7.79 (m, 1H), 7.58 (s, 1H),7.48 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.13-7.16 (m, 1H), 6.94(d, J=8.8 Hz, 2H), 5.21 (s, 2H), 3.90-3.95 (m, 1H), 3.78 (s, 3H), 2.59(d, J=7.2 Hz, 2H), 1.77 (d, J=2.4 Hz, 3H). LC/MS: mass calcd. forC₂₇H₂₃NO₄S: 457.54, found: 458.1 [M+H]⁺.

Example 79(3S)-3-(4-((3-(2-Methoxyphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 79)

(A) (3S)-Ethyl3-(4-((3-(2-methoxyphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and 2-methoxyphenylboronic acid following General ProcedureA using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in placeof K₂CO₃. LC/MS: mass calcd. for C₃₀H₂₈O₄S: 484.61, found: 502.1[M+NH₄]⁺.

(B)(3S)-3-(4-((3-(2-Methoxyphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 79) was prepared from (3S)-ethyl3-(4-((3-(2-methoxyphenyl)-benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate following General ProcedureC, using LiOH as base, EtOH in place of MeOH, a rt reaction temperatureovernight and 1N HCl for reaction acidification. ¹H NMR (DMSO-d₆) δ 8.00(d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.44 (t, J=7.2 Hz, 2H),7.31-7.33 (m, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.17 (d, J=7.8 Hz, 1H), 7.06(t, J=6.9 Hz, 1H), 6.90 (d, J=8.1 Hz, 2H), 5.18 (s, 2H), 3.90-3.95 (m,1H), 3.68 (s, 3H), 2.51 (s, 2H), 1.75 (d, J=1.8 Hz, 3H). LC/MS: masscalcd. for C₂₈H₂₄O₄S: 456.55, found: 479.2 [M+Na]⁺.

Example 80(3S)-3-(4-((3-(6-Methoxy-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 80)

(A) (3S)-Ethyl3-(4-((3-(6-methoxy-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and 6-methoxy-2-methylpyridin-3-ylboronic acid followingGeneral Procedure A using PdCl₂(dppf).CH₂Cl₂ as the palladium catalystand Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₃₀H₂₉NO₄S: 499.62,found: 522.2 [M+Na]⁺.

(B)(3S)-3-(4-((3-(6-Methoxy-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 80) was prepared from (3S)-ethyl3-(4-((3-(6-methoxy-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.22 (br. s, 1H), 8.09 (d, J=8.0 Hz,1H), 7.76 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.46(s, 1H), 7.25 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.0Hz, 1H), 5.18 (s, 2H), 3.90-3.94 (m, 4H), 2.55-2.68 (m, 2H), 2.23 (s,3H), 1.77 (d, J=2.0 Hz, 2H). LC/MS: mass calcd. for C₂₈H₂₅NO₄S: 471.57,found: 472.2 [M+H]⁺.

Example 81(3S)-3-(4-((3-(4-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 81)

(A) (3S)-Ethyl3-(4-((3-(4-methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and 4-methoxypyridin-3-ylboronic acid following GeneralProcedure A using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst andCs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₂₉H₂₇NO₄S: 485.59,found: 486.4 [M+H]⁺.

(B)(3S)-3-(4-((3-(4-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 81) was prepared from (3S)-ethyl3-(4-((3-(4-methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.23 (br. s, 1H), 8.63 (d, J=6.0 Hz,1H), 8.50 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.56 (s, 1H),7.49 (dd, J=1.2, 8.1 Hz, 1H), 7.36 (d, J=6.3 Hz, 1H), 7.25 (d, J=8.7 Hz,2H), 6.93 (d, J=8.7 Hz, 2H), 5.75 (s, 2H), 3.89-3.95 (m, 1H), 3.80 (s,3H), 2.51-2.59 (m, 2H), 1.76 (d, J=2.4 Hz, 2H). LC/MS: mass calcd. forC₂₇H₂₃NO₄S: 457.54, found: 456.1 [M−H]⁻.

Example 82(3S)-3-(4-((3-(6-Methoxy-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 82)

(A) (3S)-Ethyl3-(4-((3-(6-methoxy-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and 6-methoxy-4-methylpyridin-3-ylboronic acid followingGeneral Procedure A using PdCl₂(dppf).CH₂Cl₂ as the palladium catalystand Cs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₃₀H₂₉NO₄S: 499.62,found: 500.1 [M+H]⁺.

(B)(3S)-3-(4-((3-(6-Methoxy-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 82) was prepared from (3S)-ethyl3-(4-((3-(6-methoxy-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, at 40° C. overnight and 1N HCl for reaction acidification. ¹H NMR(DMSO-d₆) δ 8.80 (d, J=8.1 Hz, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.49 (d,J=9.6 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz,2H), 6.86 (s, 1H), 5.18 (s, 2H), 3.92-3.96 (m, 1H), 3.90 (s, 3H), 2.56(d, J=8.1 Hz, 2H), 2.05 (s, 3H), 1.77 (s, 3H). LC/MS: mass calcd. forC₂₈H₂₅NO₄S: 471.57, found: 472.1 [M+H]⁺.

Example 83(3S)-3-(4-((3-(3-Methoxypyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 83)

(A) (3S)-Ethyl3-(4-((3-(3-methoxypyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from (3S)-ethyl3-(4-((3-bromobenzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate (fromExample 11E) and 3-methoxypyridin-4-ylboronic acid following GeneralProcedure A using PdCl₂(dppf).CH₂Cl₂ as the palladium catalyst andCs₂CO₃ in place of K₂CO₃. LC/MS: mass calcd. for C₂₉H₂₇NO₄S: 485.59,found: 486.4 [M+H]⁺.

(B)(3S)-3-(4-((3-(3-Methoxypyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 83) was prepared from (3S)-ethyl3-(4-((3-(3-methoxypyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.71 (s, 1H), 8.55 (d, J=5.4 Hz, 1H),8.10-8.13 (m, 2H), 7.81-7.83 (m, 1H), 7.70 (s, 1H), 7.53 (d, J=8.4 Hz,1H), 7.26 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 5.20 (s, 2H),3.93-3.96 (m, 1H), 3.89 (s, 3H), 2.58 (d, J=7.5 Hz, 2H), 1.77 (d, J=2.4Hz, 3H). LC/MS: mass calcd. for C₂₇H₂₃NO₄S: 457.54, found: 458.3 [M+H]⁺.

Example 84(3S)-3-(4-((3-(5-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 84)

(A) To an ice-cooled solution of 6-bromo-5-methylpyridin-3-ol (500 mg,2.66 mmol) in DMF (10 mL) was added NaH (60% wt; 160 mg, 4.0 mmol) in aportionwise fashion and the resultant mixture was allowed to stir at rtfor 1 h. The mixture was then cooled to 0° C. and CH₃I (755 mg, 5.32mmol) was added in dropwise fashion. After stirring for 1 h at rt, thereaction was quenched with water (20 mL) and the mixture was extractedwith EtOAc (3×30 mL). The combined extracts were dried (Na₂SO₄),concentrated under reduced pressure and purified by silica gelchromatography (0-10% EtOAc/petroleum ether) to afford2-bromo-5-methoxy-3-methylpyridine (400 mg, 74% yield) as a white solid.LC/MS: mass calcd. for C₇H₈BrNO: 202.05, found: 202.0, 204.0 [M, M+2]⁺.

(B) (3-(5-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanolwas prepared from 2-bromo-5-methoxy-3-methylpyridine and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₆H₁₅NO₂S: 285.36, found: 286.1 [M+H]⁺.

(C) 2-(5-(Chloromethyl)benzo[b]thiophen-3-yl)-5-methoxy-3-methylpyridinewas prepared from(3-(5-methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanolfollowing General Procedure D. LC/MS: mass calcd. for C₁₆H₁₄ClNOS:303.81, found: 304.1 [M]⁺.

(D) (3S)-Ethyl3-(4-((3-(5-methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from2-(5-(chloromethyl)benzo[b]thiophen-3-yl)-5-methoxy-3-methylpyridine and(3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator,Inc., Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure E. LC/MS: mass calcd. for C₃₀H₂₉NO₄S: 499.62, found: 500.1[M+H]⁺.

(E)(3S)-3-(4-((3-(5-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 84) was prepared from (3S)-ethyl3-(4-((3-(5-methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, at 40° C. overnight and 1N HCl for reaction acidification. ¹H NMR(DMSO-d₆) δ 12.23 (br. s, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.06 (d, J=8.1Hz, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.42 (s,1H), 7.25 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 5.15 (s, 2H),3.90-3.97 (m, 1H), 3.89 (s, 3H), 2.58 (d, J=7.5 Hz, 2H), 2.24 (s, 3H),1.77 (s, 3H). LC/MS: mass calcd. for C₂₈H₂₅NO₄S: 471.57, found: 472.0[M+H]⁺.

Example 85(3R)-3-[6-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]pyridin-3-yl]hex-4-ynoicacid (Cpd 85)

(A) Enantiomeric resolution of ethyl3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 45E) was carried outby chiral super critical fluid chromatography on a ChiralPak AS-H 5μcolumn (2×25 cm) using an isocratic mobile phase [EtOH (0.2% DEA)/CO₂(50:50); 170 g/min] to afford (3R)-ethyl3-(6-hydroxypyridin-3-yl)hex-4-ynoate (RT=4.15 min)¹H NMR (CDCl₃) δ7.47-7.55 (m, 2H), 6.59 (d J=9.3 Hz, 1H), 4.09-4.19 (m, 2H), 3.89-3.95(m, 1H), 2.70 (dd, J=7.5, 15.3 Hz, 1H), 2.59 (dd, J=7.5, 15.6 Hz, 1H),1.82 (s, 3H), 1.25-1.27 (m, 3H) and (3S)-ethyl3-(6-hydroxypyridin-3-yl)hex-4-ynoate (RT=5.97 min).

(B) To an ice-cooled solution of5-hydroxymethyl-3-(2-methylphenyl)benzo[b]-thiophene (from Example 1B)(200 mg, 0.79 mmol) in DCM (20 mL) and DMF (2 mL) was added phosphoroustribromide (148 μL, 1.57 mmol) in dropwise fashion. After stirring for 1h, the mixture was neutralized to pH 6-7 with the addition of 1M aq.NaHCO₃, and the resulting mixture was extracted with DCM (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure to afford crude5-bromomethyl-3-(2-methylphenyl)benzo[b]-thiophene, which was useddirectly without purification.

(C) To a solution of 5-bromomethyl-3-(2-methylphenyl)benzo[b]-thiophenefrom the above step in toluene (10 mL) was added (3R)-ethyl3-(6-hydroxypyridin-3-yl)hex-4-ynoate (170 mg, 0.73 mmol) and Ag₂CO₃(434 mg, 1.57 mmol) and the resulting mixture was stirred at 60° C.overnight. Water (20 mL) was then added and the mixture was extractedwith EtOAc (3×20 mL). The combined organic extracts were concentratedunder reduced pressure and the resultant residue was purified by silicagel chromatography (0-20% EtOAc/petroleum ether) to afford (3R)-ethyl3-(6-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoate(80 mg, 19% yield) as colorless oil. LC/MS: mass calcd. for C₂₉H₂₇NO₃S:469.60, found: 470.3 [M+H]⁺.

(D)(3R)-3-(6-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 85) was prepared from (3R)-ethyl3-(6-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.01-8.09 (m, 2H), 7.62-7.69 (m, 2H),7.46 (dd, J=1.5, 8.4 Hz, 1H), 7.20-7.42 (m, 5H), 6.75 (d, J=8.4 Hz, 1H),5.38 (s, 2H), 3.95-4.05 (m, 1H), 2.40-2.50 (m, 2H), 2.06 (s, 3H), 1.75(d, J=2.4 Hz, 3H). LC/MS: mass calcd. for C₂₇H₂₃NO₃S: 441.54, found:442.0 [M+H]⁺.

Example 86(3S)-3-[4-[([3-[2-Methyl-4-(tetrahydrofuran-3-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid (Cpd 86)

(A) 3-(4-Bromo-3-methylphenoxy)tetrahydrofuran was prepared from4-bromo-3-methylphenol and 3-hydroxytetrahydrofuran following GeneralProcedure B using PPh₃ and DEAD. LC/MS: mass calcd. for C₁₁H₁₃BrO₂:257.12, found 257.1, 259.1 [M, M+2]⁺.

(B)(3-(2-Methyl-4-(tetrahydrofuran-3-yloxy)phenyl)benzo[b]thiophen-5-yl)methanolwas prepared from 3-(4-bromo-3-methylphenoxy)tetrahydrofuran and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₂₀H₂₀O₃S: 340.44, found: 323.1 [M−OH]⁺.

(C)3-(4-(5-(Chloromethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)tetrahydrofuranwas prepared from(3-(2-methyl-4-(tetrahydrofuran-3-yloxy)phenyl)benzo[b]-thiophen-5-yl)methanolfollowing General Procedure D. LC/MS: mass calcd. for C₂₀H₁₉ClO₂S:358.88, found: 359.1 [M]⁺.

(D) (3S)-Ethyl3-(4-((3-(2-methyl-4-(tetrahydrofuran-3-yloxy)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from3-(4-(5-(chloromethyl)benzo[b]thiophen-3-yl)-3-methylphenoxy)tetrahydrofuranand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure E. LC/MS: mass calcd. for C₃₄H₃₄O₅S: 554.70,found: 572.1 [M+NH₄]⁺.

(E)(3S)-3-(4-((3-(2-Methyl-4-(tetrahydrofuran-3-yloxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 86) was prepared from (3S)-ethyl3-(4-((3-(2-methyl-4-(tetrahydrofuran-3-yloxy)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a 35° C. reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.23 (br. m, 1H), 8.05 (d, J=8.1 Hz,1H), 7.65 (s, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.24 (d, J=8.7Hz, 2H), 7.17 (d, J=8.4 Hz, 1H), 6.84-6.93 (m, 4H), 5.17 (s, 2H),5.06-5.10 (m, 1H), 3.74-3.96 (m, 5H), 2.57 (d, J=7.5 Hz, 2H), 2.19-2.29(m, 1H), 2.09 (s, 3H), 1.97-2.05 (m, 1H) 1.77 (s, 3H). LC/MS: masscalcd. for C₃₂H₃₀O₅S: 526.64, found: 527.1 [M+H]⁺.

Example 87(3R)-3-(6-((3-(5-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 87)

(A)3-(5-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophene-5-carbaldehydewas prepared from 2-bromo-4-(2-methoxyethoxy)-1-methylbenzene (fromExample 65A) and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₉H₁₈O₃S: 326.41, found: 327.0 [M+H]⁺.

(B)(3-(5-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolwas prepared from3-(5-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophene-5-carbaldehydefollowing General Procedure F. LC/MS: mass calcd. for C₁₉H₂₀O₃S: 428.43,found: 311.1 [M−OH]⁺.

(C)5-(Bromomethyl)-3-(5-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophenewas prepared from(3-(5-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolfollowing the procedure described in Example 85B and used directly inthe following reaction.

(E) (3R)-Ethyl3-(6-((3-(5-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from5-(bromomethyl)-3-(5-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiopheneand (3R)-ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 85A)following the procedure described in Example 85C. LC/MS: mass calcd. forC₃₂H₃₃NO₅S: 543.67, found: 544.1 [M+H]⁺.

(D)(3R)-3-(6-((3-(5-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid was prepared from (3R)-ethyl3-(6-((3-(5-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 2N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.10 (d, J=2.4 Hz, 1H), 8.05 (d, J=8.1Hz, 1H), 7.68-7.73 (m, 2H), 7.45-7.49 (m, 2H), 7.26 (d, J=8.4 Hz, 1H),6.93-6.97 (m, 1H), 6.77-6.82 (m, 2H), 5.41 (s, 2H), 4.07-4.10 (m, 2H),3.96-4.02 (m, 1H), 3.63-3.66 (m, 2H), 3.30 (s, 3H), 2.59-2.65 (m, 2H),1.98 (s, 3H), 1.77 (d, J=2.1 Hz, 3H). LC/MS: mass calcd. for C₃₀H₂₉NO₅S:515.62, found: 516.3 [M+H]⁺.

Example 88(3R)-3-(6-((3-(3-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 88)

(A)(3-(3-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolwas prepared from 2-bromo-3-(2-methoxyethoxy)-1-methylbenzene (fromExample 67A) and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₉H₂₀O₃S: 428.43, found: 311.1 [M-OH]⁺.

(B)5-(Bromomethyl)-3-(3-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophenewas prepared from(3-(3-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methanolfollowing the procedure described in Example 85B and used directly inthe following reaction.

(C) (3R)-Ethyl3-(6-((3-(3-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from5-(bromomethyl)-3-(3-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiopheneand (3R)-ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 85A)following the procedure described in Example 85C. LC/MS: mass calcd. forC₃₂H₃₃NO₅S: 543.67, found: 544.1 [M+H]⁺.

(D)(3R)-3-(6-((3-(3-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid was prepared from (3R)-ethyl3-(6-((3-(3-(2-methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 2N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.09 (d, J=2.1 Hz, 1H), 8.04 (d, J=8.4Hz, 1H), 7.66-7.71 (m, 2H), 7.47 (dd, J=1.5, 8.4 Hz, 1H), 7.41 (s, 1H),7.26 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H),6.77 (d, J=8.7 Hz, 1H), 5.39 (s, 2H), 4.15-4.19 (m, 2H), 3.96-4.01 (m,1H), 3.71-3.74 (m, 2H), 3.35 (s, 3H), 2.54-2.61 (m, 2H), 1.92 (s, 3H),1.76 (d, J=2.1 Hz, 3H). LC/MS: mass calcd. for C₃₀H₂₉NO₅S: 515.62,found: 514.1 [M−H]⁻.

Example 89(3R)-3-(6-((3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 89)

(A)2-(5-(Bromomethyl)benzo[b]thiophen-3-yl)-5-(2-methoxyethoxy)-3-methylpyridinewas prepared from(3-(5-(2-methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 48B) following the procedure described in Example 85B andused directly in the following reaction. LC/MS: mass calcd. forC₁₈H₁₈BrNO₂S: 392.31, found: 392.2, 394.2 [M, M+2]⁺.

(B) (3R)-Ethyl3-(6-((3-(5-(2-methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from2-(5-(bromomethyl)benzo[b]thiophen-3-yl)-5-(2-methoxyethoxy)-3-methylpyridineand (3R)-ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 85A)following the procedure described in Example 85C. LC/MS: mass calcd. forC₃₂H₃₃NO₅S: 544.66, found: 545.3 [M+H]⁺.

(C)(3R)-3-(6-((3-(5-(2-methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid was prepared from (3R)-ethyl3-(6-((3-(5-(2-methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.25 (br. m, 1H), 8.28 (d, J=2.4 Hz,1H), 8.12 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.70-7.74 (m,2H), 7.44-7.49 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 5.40 (s, 2H), 4.25 (t,J=4.0 Hz, 2H), 3.99-4.00 (m, 1H), 3.72 (t, J=4.4 Hz, 2H), 3.32 (s, 3H),2.65-2.67 (m, 2H), 2.24 (s, 3H), 1.78 (s, 3H). LC/MS: mass calcd. forC₃₀H₂₉NO₅S: 516.61, found: 517.1 [M+H]⁺.

Example 90(3R)-3-(6-((3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 90)

(A) (3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methanol wasprepared from 4-bromo-2-chloro-5-methylpyridine and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₅H₁₂ClNOS: 289.78, found: 290.0, 292.0[M, M+2]⁺.

(B) 2-Chloro-4-(5-(bromomethyl)benzo[b]thiophen-3-yl)-5-methylpyridinewas prepared from(3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methanolfollowing the procedure described in Example 85B and used directly inthe following reaction.

(C) (3R)-Ethyl3-(6-((3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from2-chloro-4-(5-(bromomethyl)benzo[b]thiophen-3-yl)-5-methylpyridine and(3R)-ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 85A)following the procedure described in Example 85C. LC/MS: mass calcd. forC₂₈H₂₅ClN₂O₃S: 505.03, found: 505.2, 507.2 [M, M+2]⁺.

(D)(3R)-3-(6-((3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid was prepared from (3R)-ethyl3-(6-((3-(2-chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 12.28 (br. s, 1H), 8.44 (s, 1H),8.07-8.14 (m, 2H), 7.97 (s, 1H), 7.73 (dd, J=2.7, 8.7 Hz, 1H), 7.53 (d,J=7.8 Hz, 2H), 7.44 (s, 1H), 6.81 (d, J=8.7 Hz, 1H), 5.43 (s, 2H), 4.00(q, J=6.3 Hz, 1H), 2.65 (dd, J=1.8, 7.8 Hz, 2H), 2.07 (s, 3H), 1.78 (d,J=2.4 Hz, 3H). LC/MS: mass calcd. for C₂₆H₂₁ClN₂O₃S: 476.98, found:477.1, 479.1 [M, M+2]⁺.

Example 91(3S)-3-(4-((3-(3-Methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 91)

(A) (3-(3-Methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methanol wasprepared from 2-bromo-3-methoxypyridine and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃ at a reaction temperature of 80° C. overnight. LC/MS: mass calcd.for C₁₅H₁₃NO₂S: 271.33, found: 272.1 [M+H]⁺.

(B) 2-(5-(Chloromethyl)benzo[b]thiophen-3-yl)-3-methoxypyridine wasprepared from (3-(3-methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methanolfollowing General Procedure D. LC/MS: mass calcd. for C₁₅H₁₂ClNOS:289.78, found: 290.0 [M]⁺.

(C) (3S)-Ethyl3-(4-((3-(3-methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from2-(5-(chloromethyl)benzo[b]thiophen-3-yl)-3-methoxypyridine and(3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator,Inc., Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure E. LC/MS: mass calcd. for C₂₉H₂₇NO₄S: 485.59, found: 486.1[M+H]⁺.

(D)(3S)-3-(4-((3-(3-Methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 91) was prepared from (3S)-ethyl3-(4-((3-(3-methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a 30° C. reaction temperature overnight and 1N HCl for reactionacidification. Further purification was carried out by preparative HPLCon a Waters SunFire™ Prep C18, 5μ column (19×100 mm) using anacetonitrile/water (0.5% NH₄HCO₃) gradient (55-75%). ¹H NMR (DMSO-d₆) δ8.30 (d, J=8.7 Hz, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 8.04 (d, J=8.4 Hz,1H), 7.61 (d, J=9.9 Hz, 1H), 7.39-7.48 (m, 2H), 7.12 (d, J=8.7 Hz, 2H),6.92 (d, J=8.7 Hz, 2H), 5.17 (s, 2H), 3.91-3.96 (m, 2H), 3.81 (s, 3H),2.37-2.44 (m, 2H), 1.74 (s, 3H). LC/MS: mass calcd. for C₂₇H₂₃NO₄S:457.54, found: 458.2 [M+H]⁺.

Example 92(3R)-3-(6-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)pyridine-3-yl)hex-4-ynoicacid (Cpd 92)

(A)(3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methanolwas prepared from 3-bromo-5-(2-methoxyethoxy)-2-methylpyridine (fromExample 49A) and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and Cs₂CO₃ in place ofK₂CO₃. LC/MS: mass calcd. for C₁₈H₁₉NO₃S: 329.41, found: 330.0 [M+H]⁺.

(B)3-(5-(Bromomethyl)benzo[b]thiophen-3-yl)-5-(2-methoxyethoxy)-2-methylpyridinewas prepared from(3-(5-(2-methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methanolfollowing the procedure described in Example 85B and used directly inthe following reaction. LC/MS: mass calcd. for C₁₈H₁₈BrNO₂S: 392.41,found: 391.9, 393.9 [M, M+2]⁺.

(C) (3R)-Ethyl3-(6-((3-(5-(2-methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatewas prepared from3-(5-(bromomethyl)benzo[b]thiophen-3-yl)-5-(2-methoxyethoxy)-2-methylpyridineand (3R)-ethyl 3-(6-hydroxypyridin-3-yl)hex-4-ynoate (from Example 85A)following the procedure described in Example 85C. LC/MS: mass calcd. forC₃₁H₃₂N₂O₅S: 544.66, found: 545.1 [M+H]⁺.

(D)(3R)-3-(6-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid (Cpd 92) was prepared from (3R)-ethyl3-(6-((3-(5-(2-methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a 35° C. reaction temperature overnight and 2N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.28 (d, J=3.0 Hz, 1H), 8.09-8.11 (m,2H), 7.83 (s, 1H), 7.71 (dd, J=2.4, 8.4 Hz, 1H), 7.48-7.53 (m, 2H), 7.29(d, J=3.0 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 5.42 (s, 2H), 4.17-4.20 (m,2H), 3.95-4.00 (m, 1H), 3.65-3.68 (m, 2H), 3.30 (s, 3H), 2.63-2.66 (m,2H), 2.19 (s, 3H), 1.77 (d, J=2.4 Hz, 3H). LC/MS: mass calcd. forC₂₉H₂₈N₂O₅S: 516.61, found: 517.3 [M+H]⁺.

Example 93(3S)-3-(4-((3-(6-Chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid (Cpd 93)

(A) (3-(6-Chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanol wasprepared from 2-bromo-6-chloro-3-methylpyridine and(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methanol(from Example 41A) following General Procedure A using PdCl₂(dppf)CH₂Cl₂as the palladium catalyst and Cs₂CO₃ in place of K₂CO₃. LC/MS: masscalcd. for C₁₅H₁₂ClNOS: 289.78, found: 290.0, 292.0 [M, M+2]⁺.

(B) 6-Chloro-2-(5-(chloromethyl)benzo[b]thiophen-3-yl)-3-methylpyridinewas prepared from(3-(6-chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanolfollowing General Procedure D and used directly in the following step.

(C) (3S)-Ethyl3-(4-((3-(6-chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from6-chloro-2-(5-(chloromethyl)benzo[b]thiophen-3-yl)-3-methylpyridine and(3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator,Inc., Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure E, using K₂CO₃ in place of Cs₂CO₃, DMF as solvent in place ofMeCN and a reaction temperature of 60° C. overnight. LC/MS: mass calcd.for C₂₉H₂₆ClNO₃S: 504.04, found: 504.1 [M]⁺.

(D)3-(4-((3-(6-Chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 93) was prepared from (3S)-ethyl3-(4-((3-(6-chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. Further purification was carried out by reversed phaseflash chromatography on an Agela Technologies C18 cartridge, (120 g,20-35μ, 100 Å) using an acetonitrile/water gradient (35-90%). ¹H NMR(DMSO-d₆) δ 12.22 (br. s, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.05 (s, 1H),7.89 (dd, J=0.8, 8.7 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.48-7.54 (m, 2H),7.22-7.29 (m, 2H), 6.92-6.98 (m, 2H), 5.19 (s, 2H), 3.89-3.96 (m, 1H),2.58 (d, J=7.6 Hz, 2H), 2.24 (s, 3H), 1.77 (d, J=2.4 Hz, 3H). LC/MS:mass calcd. for C₂₇H₂₂ClNO₃S: 475.99, found: 475.9 [M]⁺.

Example 94(3S)-3-(4-((3-(6-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 94)

(A) A mixture of(3-(6-chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanol (300mg, 1.04 mmol, from Example 93A), DMSO (10 mL) and sodium methoxide inmethanol (4 ml) was heated for 30 min in a microwave reactor at 100° C.After cooling to rt, the reaction was quenched with water (50 mL) andthe mixture was extracted with EtOAc (3×50 mL). The combined extractswere concentrated under reduced pressure to afford crude6-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-5-methylpyridin-2-ol as blackoil, which was used directly without further purification. LC/MS: masscalcd. for C₁₅H₁₃NO₂S: 271.33, found: 272.0 [M+H]⁺.

(B) To a mixture of6-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-5-methylpyridin-2-ol (340 mg,1.25 mmol) and Ag₂CO₃ (1.04 g, 3.76 mmol), in toluene (10 ml), was addediodomethane (0.53 g, 3.76 mmol). After stirring overnight at 45° C., themixture was filtered and the filtrate was concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography eluting with EtOAc/petroleum ether (0-30%) to afford(3-(6-methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanol (121mg, 28%), as a colorless oil. LC/MS: mass calcd. for C₁₆H₁₅NO₂S: 285.36,found: 286.0 [M+H]⁺.

(C) 2-(5-(Chloromethyl)benzo[b]thiophen-3-yl)-6-methoxy-3-methylpyridinewas prepared from(3-(6-methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methanolfollowing General Procedure D, and used directly.

(D) (3S)-Ethyl3-(4-((3-(6-methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from2-(5-(chloromethyl)benzo[b]thiophen-3-yl)-6-methoxy-3-methylpyridine and(3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available from Synnovator,Inc., Research Triangle Park, N.C.; Cat. # PB05708) following GeneralProcedure E. LC/MS: mass calcd. for C₃₀H₂₉NO₄S: 499.62, found: 500.3[M+H]⁺.

(F)(3S)-3-(4-((3-(6-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 94) was prepared from (3S)-ethyl3-(4-((3-(6-methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using LiOH as base, EtOH in place ofMeOH, a rt reaction temperature overnight and 1N HCl for reactionacidification. ¹H NMR (DMSO-d₆) δ 8.07 (d, J=8.4 Hz, 1H), 7.78 (s, 1H),7.95 (d, J=7.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4, 1.6 Hz,1H), 7.20-7.28 (m, 2H), 6.88-6.96 (m, 2H), 6.80 (d, J=8.3 Hz, 1H), 5.20(s, 2H), 3.90-3.95 (m, 1H), 3.77 (s, 3H), 2.57 (dd, J=7.6, 1.2 Hz, 2H),2.22 (s, 3H), 1.76 (d, J=2.4 Hz, 3H). LC/MS: mass calcd. for C₂₈H₂₅NO₄S:471.57, found: 472.2 [M+H]⁺.

Example 95(3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 95)

(A) Methyl 3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene-5-carboxylatewas prepared from methyl 3-bromobenzo[b]thiophene-5-carboxylate and4-hydroxy-2-methylphenylboronic acid following General Procedure A usingPdCl₂(dppf).CH₂Cl₂ as the palladium catalyst and TEA in place of K₂CO₃and EtOH as solvent at a temperature of 80° C. overnight. LC/MS: masscalcd. for C₁₇H₁₄O₃S: 298.36, found: 299.0, [M+H]⁺.

(B) To a solution of methyl3-(4-hydroxy-2-methylphenyl)benzo[b]thiophene-5-carboxylate (3.9 g, 13.1mmol) and pyridine (3.10 g, 39.2 mmol) in DCM (50 ml), was added Tf₂O(5.53 g, 19.6 mmol) in dropwise fashion. After stirring overnight at rt,the mixture was diluted with water (40 mL) and extracted with EtOAc(3×100 mL). The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography eluting withEtOAc/petroleum ether (0-15%) to afford methyl3-(2-methyl-4-(trifluoromethylsulfonyloxy)phenyl)benzo[b]thiophene-5-carboxylate(5.0 g, 80%), as a colorless oil. LC/MS: mass calcd. for C₁₈H₁₃F₃O₅S₂:430.42, found: 431.1 [M+H]⁺.

(C) 9-Borabicyclo[3.3.1]nonane (0.5 M solution in THF; 20.5 ml, 10.25mmol) was added to tert-butyl 4-methylenepiperidine-1-carboxylate (2.02g, 10.24 mmol) under an inert atmosphere of nitrogen and the resultantsolution was stirred at 60° C. for 1 h. Methyl3-(2-methyl-4-(trifluoromethylsulfonyloxy)phenyl)benzo[b]thiophene-5-carboxylate(4 g, 9.29 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (22.7 mg, 0.028 mmol), K₂CO₃ (12.8g, 92.75 mmol), DMF (40 ml) and H₂O (4 ml) were added, and the resultingsolution was stirred at 60° C. for an additional 3 h. The mixture wasthen extracted with EtOAc (3×100 mL) and the combined organic extractswere washed with brine, dried (Na₂SO₄) and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography eluting with EtOAc/petroleum ether (0-15%) to affordtert-butyl4-(4-(5-(methoxycarbonyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylate(3.51 g, 70.8%) as colorless oil. LC/MS: mass calcd. for C₂₈H₃₃NO₄S:479.63, found: 480.3 [M+H]⁺.

(D) To a cooled (−60° C.) solution of tert-butyl4-(4-(5-(methoxycarbonyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylate(3.51 g, 7.32 mmol) in toluene (35 mL) was added DIBAL-H (1M in toluene;14.6 mL, 14.6 mmol) and the resultant solution was stirred at rt for 2h. The mixture was quenched by the addition of MeOH (20 mL), dilutedwith H₂O (100 mL) then extracted with EtOAc (3×100 mL) and the combinedorganic extracts were washed with brine, dried (Na₂SO₄) and concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography eluting with EtOAc/petroleum ether (0-15%) to affordtert-butyl4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylbenzyl)piperidine-1-carboxylate(1.91 g, 57.8%) as colorless oil. LC/MS: mass calcd. for C₂₇H₃₃NO₃S:451.62, found: 452.2 [M+H]⁺.

(E) (3S)-tert-Butyl4-(4-(5-((4-(1-ethoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)benzo-[b]thiophen-3-yl)-3-methylbenzyl)piperidine-1-carboxylatewas prepared from tert-butyl4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylbenzyl)piperidine-1-carboxylateand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure B using (Bu)₃P and ADDP at a reactiontemperature of 70° C. overnight. LC/MS: mass calcd. for C₄₁H₄₇NO₅S:665.88, found: 666.3 [M+H]⁺.

(F) To a solution of (3S)-tert-butyl4-(4-(5-((4-(1-ethoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)benzo-[b]thiophen-3-yl)-3-methylbenzyl)piperidine-1-carboxylate(900 mg, 1.35 mmol) in dioxane (15 mL) was added 4N HCl/dioxane (4 mL,16 mmol) and the resulting solution was stirred overnight. The solutionpH was adjusted to 6 with aq. NaHCO₃ and the mixture was extracted withEtOAc (3×100 mL). The combined extracts were concentrated under reducedpressure and the resultant residue was purified by preparative HPLC on aWaters SunFire™ Prep C18, 5μ column (19×100 mm) using a gradient ofacetonitrile/water (0.05% TFA) (25-70%) as eluent to afford (3S)-ethyl3-(4-((3-(2-methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(TFA salt) (134 mg, 14.4%) as an off white solid. LC/MS: mass calcd. forC₃₆H₃₉NO₃S: 565.76, found: 566.3 [M+H]⁺.

(G)(3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 95) was prepared from (3S)-ethyl3-(4-((3-(2-methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate(TFA salt) following General Procedure C, using LiOH as base, THF/water(1:1) as solvent, a rt reaction temperature overnight and 2N HCl forreaction acidification. The residue obtained was purified by preparativeHPLC on a Waters SunFire™ Prep C18, 5μ column (19×100 mm) using agradient of acetonitrile/water (0.05% TFA) (25-70%) as eluent. ¹H NMR(CD₃OD) δ 7.88 (d, J=8.0 Hz, 1H), 7.35-7.39 (m, 2H), 7.17-7.27 (m, 3H),7.03-7.12 (m, 3H), 6.78-6.80 (m, 2H), 5.07 (s, 2H), 3.96-3.97 (m, 1H),3.27 (m, 2H), 2.81-2.89 (m, 2H), 2.51-2.62 (m, 3H), 2.37-2.45 (m, 1H),2.01 (s, 3H), 1.81-1.86 (m, 3H), 1.76 (s, 3H), 1.26-1.45 (m, 2H). LC/MS:mass calcd. for C₃₄H₃₅NO₃S: 537.71, found: 536.1[M−H]⁻.

Example 96(3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 96)

(A) tert-Butyl4-(4-(5-(methoxycarbonyl)benzo[b]thiophen-3-yl)-3-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylatewas prepared from methyl3-(2-methyl-4-(trifluoromethylsulfonyloxy)phenyl)benzo[b]thiophene-5-carboxylate(from Example 95B) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylatefollowing General Procedure A using Pd(PPh₃)₄ as the palladium catalystand Na₂CO₃ in place of K₂CO₃ at a temperature of 80° C. overnight.LC/MS: mass calcd. for C₂₇H₂₉NO₄S: 463.59, found: 486.2 [M+Na]⁺.

(B) A mixture of tert-butyl4-(4-(5-(methoxycarbonyl)benzo[b]thiophen-3-yl)-3-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate(4.5 g, 9.71 mmol) and Pd/C (10%, 500 mg) in MeOH (100 mL) washydrogenated overnight at rt. The mixture was then filtered and thefiltrate was concentrated under reduced pressure to afford tert-butyl4-(4-(5-(methoxycarbonyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylate(4.3 g, 94%) as light-yellow oil. LC/MS: mass calcd. for C₂₇H₃₁NO₄S:465.60, found: 488.2 [M+Na]⁺.

(C) tert-Butyl4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylatewas prepared from tert-butyl4-(4-(5-(methoxycarbonyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylatefollowing the procedure described in Example 95D. EtOAc/petroleum ether(0-20%) was used as eluent for the silica gel chromatographicpurification. LC/MS: mass calcd. for C₂₆H₃₁NO₃S: 437.59, found: 460.15[M+Na]⁺.

(D) tert-Butyl4-(4-(5-((4-((4-((3S)-1-ethoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylatewas prepared from tert-butyl4-(4-(5-(hydroxymethyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylateand (3S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (available fromSynnovator, Inc., Research Triangle Park, N.C.; Cat. # PB05708)following General Procedure B using (Bu)₃P and ADDP at a reactiontemperature of 60° C. overnight. LC/MS: mass calcd. for C₄₀H₄₅NO₅S:651.85, found: 652.4 [M+H]⁺.

(E) (3S)-Ethyl3-(4-((3-(2-methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from tert-Butyl4-(4-(5-((4-((4-(3S)-1-ethoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)benzo[b]thiophen-3-yl)-3-methylphenyl)piperidine-1-carboxylatefollowing the procedure described in Example 95F. LC/MS: mass calcd. forC₃₅H₃₇NO₃S: 551.74, found: 552.25 [M+H]⁺.

(F)(3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 96) was prepared from (3S)-ethyl3-(4-((3-(2-methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using NaOH as base, THF/water (1:1) assolvent, a rt reaction temperature overnight and 1N HCl for reactionacidification. Product purification was carried out by silica gelchromatography using MeOH/DCM (0-25%) as eluent. ¹H NMR (DMSO-d₆) δ 8.01(s, 1H), 7.68 (s, 1H), 7.39-7.41 (m, 1H), 7.15-7.29 (m, 4H), 7.04-7.06(m, 2H), 6.81-6.87 (m, 2H), 5.20 (s, 2H), 3.98-4.01 (m, 1H), 3.10-3.18(m, 2H), 2.67-2.70 (m, 3H), 2.31-2.46 (m, 2H), 2.00 (s, 3H), 1.72-1.75(m, 7H). LC/MS: mass calcd. for C₃₃H₃₃NO₃S: 523.68, found: 524.2 [M+H]⁺.

Example 973-(4-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 97)

(A) Methyl3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatewas prepared from 5-(chloromethyl)-3-(2-methylphenyl)benzo[b]thiophene(Example 2a, Step F) and methyl 3-(4-hydroxyphenyl)hex-4-ynoate(available from Oxchem Corporation, Irwindale, Calif.; Cat. # AX8267763)following General Procedure E, at a reaction temperature of 40° C.LC/MS: mass calcd. for C₂₉H₂₆O₃S: 454.16, found: 477.1 [M+Na]⁺.

(B)3-(4-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid (Cpd 97) was prepared from methyl3-(4-((4-(3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoatefollowing General Procedure C, using NaOH as a base, at a 35° C.reaction temperature for 2 h and 2M citric acid for reactionacidification. ¹H NMR (CDCl₃) δ 7.92 (d, J=9.1 Hz, 1H), 7.39-7.51 (m,2H), 7.24-7.36 (m, 7H), 6.89 (d, J=8.6 Hz, 2H), 5.08 (s, 2H), 4.03 (m,1H), 2.78 (dd, J=15.7, 8.6 Hz, 1H), 2.68 (dd, J=15.9, 6.8 Hz, 1H), 2.15(s, 3H), 1.82 (d, J=2.0 Hz, 3H). LC/MS: mass calcd. for C₂₈H₂₄O₃S:440.14, found: 463.2 [M+Na]⁺.

Biological Examples In Vitro Assays Example 1 GPR40 Calcium Flux Assay

Compounds were tested in a calcium flux assay using transfected HEK293cells stably expressing either human GPR40 or rat GPR40. Human GPR40expressing cells were cultured in DMEM-High Glucose media supplementedwith 10% fetal bovine serum, 1×L-Glutamine, 1×Penicillin/Streptomycinand 500 μg/mL G418. Rat GPR40 expressing cells were cultured inDMEM-High Glucose media supplemented with 10% fetal bovine serum and 1μg/mL puromycin. Cells were plated into poly-D-lysine coated 384-wellplates and cultured overnight in a 37° C. humidified tissue cultureincubator under 5% CO₂/90% O₂ atmosphere. On the day of the experiment,the culture media was replaced with assay buffer (HBSS, 20 mM HEPES,0.1% BSA) and the cells incubated at 37° C. for 1 h. Calcium-sensitivefluorescent dye (Fluo 8 No-Wash Calcium Dye, ABD Bioquest) was thenadded and the cells incubated for another 30 min at 37° C. followed by15 min at room temperature while protected from the light. The cellplate and a plate of diluted compounds of Formula (I) were loaded into afluorescent plate reader that added compounds onto the cells whilemeasuring the fluorescence intensity of each well. The plate readerrecorded fluorescence intensity at 1 second intervals for 8 min andprovided the data for analysis in an Excel format. EC₅₀ values werecalculated using Prism (GraphPad) software. Resultant mean data areshown in Table 2.

TABLE 2 Ca²⁺ Mobilization Data hGPR40 Ca²⁺ Cpd No Assay EC50 (μM) 10.007 2 0.005 3 0.005 4 0.003 5 0.023 6 0.015 7 0.007 8 0.02 9 0.017 100.041 11 0.016 12 0.009 13 0.007 14 0.009 15 0.002 16 0.005 17 0.006 180.011 19 0.008 20 0.005 21 0.008 22 0.008 23 0.01 24 0.009 25 0.024 260.018 27 0.02 28 0.012 29 0.034 30 0.006 31 0.014, 0.048 32 0.036 330.015 34 0.025 35 0.026 36 0.043 37 0.017 38 0.019 39 0.046 40 0.015 410.021 42 0.012 43 0.031 44 0.022 45 0.013 46 0.018 47 0.02 48 0.01 490.009 50 0.012 51 0.006 52 0.019 53 0.89 54 0.044 55 0.033 56 0.034 570.017 58 0.014 59 0.014 60 0.070 61 0.016 62 0.010 63 0.010 64 0.021 650.011 66 0.014 67 0.009 68 0.019 69 0.015 70 0.5 71 0.012 72 1.33 730.013 74 0.18 75 0.007 76 0.83 77 0.016; 0.006; 0.005 78 0.009 79 0.02880 0.02 81 0.011 82 0.037 83 0.010 84 0.052 85 0.007; 0.006 86 0.008 870.011 88 0.008 89 0.02 90 0.015 91 0.017 92 0.013 93 0.015 94 0.015 950.004 96 0.008 97 0.004 98 0.16

In-Vivo Assays Oral Glucose Tolerance Test

Male SD rats (200-250 g) were housed 2 per cage in atemperature-controlled room with a 12-hour light/dark cycle. They wereallowed ad libitum access to water and fed with normal rodent chow. Thenight before the oral glucose tolerance test (oGTT), the rats weretransferred to clean cages and fasted overnight. On the morning of theoGTT, the rats were weighed and randomized into groups based on fastedblood glucose and body weight. Rats were dosed with vehicle (0.5%methocel) or compounds (10 mg/kg, po) thirty to forty min prior to theoGTT (glucose, 2 g/kg, po). Blood was collected from the tail vein at 0,10, 30, 60 and 120 minutes after glucose challenge to measure bloodglucose; plasma was used to determine insulin levels. The area under thecurve for blood glucose excursion was calculated from t=0 to t 120minutes. Percent lowering of glucose was calculated from the AUC datawith respect to the vehicle-treated group. Resultant data are shown inTable 3.

TABLE 3 Percent Lowering of Glucose Cpd No. (AUC compound vs. AUCVehicle) 2 72% 16 76% Note: AUC = Integrated area under the glucoseexcursion curve from t = 0 to t = 120 minutes.

Oral Glucose Tolerance Test: Canagliflozin Combination with GPR40Agonist

We have evaluated the blood glucose (BG) lowering effect ofcanagliflozin (Cana) combined with a GPR40 agonist Cpd 2 in SD ratstudies. Overnight fasted SD rats received either a single treatment ofCana or Cpd 2 or a combination of both. An oral glucose tolerance test(OGTT) was followed at 60 min post compound administration. Bloodglucose area under the curve (AUC) was determined from samples taken at0-120 min during OGTT. The two-sided Z Test and Delta method wereapplied to statistically determine the treatment additivity ofcombinations using blood glucose AUC values. Results indicated thetreatments were additive in the combinations of Canagliflozin at 1 or 3mg/kg and Cpd 2 at 0.3 or 1 mg/kg. However, additivity was not detectedin the combinations of Canagliflozin at 10 mg/kg with each dose of Cpd2, likely due to Canagliflozin at 10 mg/kg markedly lowering bloodglucose during OGTT, and thus limiting the efficacy of combinationtreatment since both Canagliflozin and Cpd 2 effects areglucose-dependent. Data suggests that combinations of low doses ofCanagliflozin and a GPR40 agonist may provide additive blood glucoselowering effect during OGTT.

Method

Test Article and Control: The test articles named below for thesestudies were obtained from internal synthesis.

Canagliflozin Cpd 2 (cpd of Formula (I) Preparation of Test Article andControls

-   A. The formulation of Canagliflozin was prepared by directly adding    the required amount of 0.5% HPMC to the compound and stirring    overnight.-   B. The formulation of Cpd 2 was prepared following steps listed    below:    -   a. One equivalent (amount of compound/compound MW) of 1N NaOH        was added to dry compound to enhance water solubility (due to        compound itself is a carboxylic acid).    -   b. The required volume of 0.5% HPMC was then added;    -   c. The compound was vortexed and sonicated (without heat) for a        minimum of 10 minutes.    -   d. The compound was then allowed to stir overnight.-   C. For the formulation of combination of Canagliflozin (Cana) and    Cpd 2:    -   a. First, a formulation of double concentrations of each        compound was prepared.

Dosing Formulation Total Compound Add 1N Treated Compound ConcentrationConcentration in Total volume NaOH Group Cpd 2 0.3 mg/kg   0.03 mg/Ml 1.2 mg/40 mL  0.003 mL Group 2 Cpd 2 0.3 mg/kg   0.06 mg/mL  4.2 mg/70mL  0.010 mL Group 7, 8, 9 Cpd 2 1 mg/kg 0.1 mg/mL  4 mg/40 mL 0.009 mLGroup 3 Cpd 2 1 mg/kg 0.2 mg/mL 24 mg/70 mL 0.055 mL Group 10, 11, 12Cana 1 mg/kg 0.1 mg/mL  4 mg/40 mL NA Group 4 Cana 1 mg/kg 0.2 mg/mL 10mg/50 mL NA Group 7, 10 Cana 3 mg/kg 0.3 mg/mL 12 mg/40 mL NA Group 5Cana 3 mg/kg 0.6 mg/mL 30 mg/50 mL NA Group 8, 11 Cana 10 mg/kg    1mg/mL 40 mg/40 mL NA Group 6 Cana 10 mg/kg    2 mg/mL 100 mg/50 mL  NAGroup 9, 12

-   -   b. Right before dosing, the double-concentrated formulation of        Cpd 2 was mixed with an equal volume of the double-concentrated        formulation of Canagliflozin, such that each compound was as 1×        concentration.

-   D. The dosing volume for all the experiments was 10 mL/kg

Experimental Design

Male SD rats (225-245 g of body weight, purchased from Charles River)were used in this study. SD rats were housed 2 per cage in atemperature-controlled room with 12-hour light/dark cycle (6 am-6 pmlights on). They are allowed ad libitum access to water and fed withPurina 5K75 (LabDiet, St. Louis, Mo.).

SD rats were fasted overnight. In the morning of the next day, theserats were grouped into the following 12 groups based on their fastedblood glucose levels determined by a glucometer (LifeScan, NewBrunswick, N.J.) and body weight.

TABLE 4 Treatment groups (n = 8 per group) Group Treatment Animal # 1Vehicle: 10 mL/kg of body weight 1 #-8 # 2 Cpd 2 0.3 mg/kg of bodyweight  9 #-16 # 3 Cpd 2 1.0 mg/kg of body weight 17 #-24 # 4 Cana 1mg/kg of body weight 25 #-32 # 5 Cana 3 mg/kg of body weight 33 #-40 # 6Cana 10 mg/kg of body weight 41 #-48 # 7 Cpd 2 0.3 mg/kg combined withCana 1 mg/kg 49 #-56 # 8 Cpd 2 0.3 mg/kg combined with Cana 3 mg/kg 57#-64 # 9 Cpd 2 0.3 mg/kg combined with Cana 10 mg/kg 65 #-72 # 10 Cpd 21 mg/kg combined with Cana 1 mg/kg 73 #-80 # 11 Cpd 2 1 mg/kg combinedwith Cana 3 mg/kg 81 #-88 # 12 Cpd 2 1 mg/kg combined with Cana 10 mg/kg89 #-96 #

-   -   Dose volume=10 mg/kg of body weight        At −60 minutes BG values were collected via tail bleeding. Next,        rats were dosed orally with vehicle or compounds in vehicle.        Then, at 0 minutes, rats were bled via tail vein to determine BG        levels and dosed orally with glucose (2 g/kg; 50% glucose, 4        mL/kg). Blood samples were collected at 30, 60, and 120 minutes        after oral glucose administration for BG determination.

Data Analysis

Statistical analysis were performed using the program Prism (Graphpad,Monrovia, Calif.) with either a repeated measures 1-way ANOVA (glucoseand insulin curves with Tukey's post-test) or a one-way ANOVA andTukey's multiple comparison test (AUC, delta AUC and percent vehicle).All data are presented as the mean±standard error of the mean (SEM).AUC=Integrated area under the glucose excursion curve from t=0 to t=120minutes.

The two-sided Z Test and Delta method was applied to statisticallydetermine the treatment additivity of combinations.

Results

TABLE 5 The effect of the Combination of Cpd 2 and Canagliflozin onblood glucose levels during OGTT in SD rat after single-dose treatment(Data as mean ± SE, n = 8 each group) Blood glucose AUC Blood glucose(mg/dl) mg/dL/120 % of Treatment BW(g) −60 0 30 60 120 min VehicleVehicle 268.9 ± 4.5 65.8 ± 3.1 82.9 ± 4.7  178.6 ± 10.4 188.8 ± 5.3129.5 ± 6.2 18,981 ± 518 100.0 ± 2.7%   Cpd 2 263.8 ± 2.0 66.3 ± 4.186.1 ± 4.2 149.0 ± 4.3 153.1 ± 4.2 103.3 ± 4.0 15,750 ± 244 83.0 ± 1.3%*0.3 mpk Cpd 2 267.1 ± 4.4 65.5 ± 2.6 76.1 ± 5.0 132.3 ± 6.4 139.6 ± 7.3102.4 ± 4.8 14,464 ± 554 76.2 ± 2.9%* 1 mpk Cana 263.3 ± 2.3 66.0 ± 2.376.9 ± 2.3 162.8 ± 6.5 177.8 ± 4.0 135.5 ± 8.2 18,099 ± 551 95.4 ± 2.9%1 mpk Cana 264.3 ± 1.7 66.1 ± 2.9 85.1 ± 3.0 140.5 ± 5.1 156.4 ± 4.0125.1 ± 9.7 16,204 ± 412 85.4 ± 2.2%* 3 mpk Cana 267.0 ± 2.9 63.0 ± 3.973.6 ± 4.4  91.9 ± 6.4 103.5 ± 5.4  95.1 ± 3.7 11,400 ± 459 60.1 ± 2.4%*10 mpk Cpd 2 0.3 mpk/ 268.9 ± 3.4 69.8 ± 3.4 82.1 ± 5.6 122.5 ± 7.8130.0 ± 5.9 101.1 ± 2.9 13,791 ± 505 72.7 ± 2.7%* Cana 1 mpk Cpd 2 0.3mpk/ 267.3 ± 3.9 68.6 ± 4.0 80.1 ± 3.0 118.9 ± 4.7 121.3 ± 5.7 104.1 ±4.3 13,348 ± 420 70.3 ± 2.2%* Cana 3 mpk Cpd 2 0.3 mpk/ 262.8 ± 1.8 65.5± 2.0 74.4 ± 3.9  87.6 ± 3.9  93.0 ± 4.1 100.6 ± 1.9 10,946 ± 287 57.7 ±1.5%* Cana 10 mpka Cpd 2 1 mpk / 257.5 ± 2.2 68.4 ± 2.1 71.6 ± 4.7 123.0± 5.1 129.3 ± 3.5 104.3 ± 3.3 13,708 ± 425 72.2 ± 2.2%* Cana 1 mpk Cpd 21 mpk / 267.6 ± 2.7 62.9 ± 3.2 72.1 ± 2.8 106.1 ± 3.4 119.5 ± 2.8  95.6± 5.1 12,512 ± 287 65.9 ± 1.5%* Cana 3 mpk Cpd 2 1 mpk/ 261.3 ± 3.0 69.1± 3.4 68.0 ± 3.7 83.0 ± 3.0  87.5 ± 5.7  94.5 ± 3.2 10,283 ± 367 54.2 ±1.9%* Cana 10 mpk a: One rat died due to glucose dose-error. thus OGTTdata (0-120 min) n = 7. *: P < 0.05, compared with that in vehicle group(One-way ANOVA, Dunnett's multiple comparisons test

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. A pharmaceutical composition comprising (a) a GPR40 agonistand (b) an SGLT2 inhibitor; wherein the GPR40 agonist is a compound ofFormula (I)

wherein ring W is phenyl or pyridyl; A is —CH₂O— or —OCH₂—; Z is CH orN; R₆ is hydrogen; R₁ is selected from hydrogen or methylacetylenyl; orR₁ and R₆ are taken together to form a spirofused 3-hydroxycyclobutyl ora spirofused 3-oxocyclobutyl; R₂ is selected from hydrogen or methyl; R₃is hydrogen, chloro, or a substituent selected from the group consistingof C₁₋₃alkyl, hydroxy, 1,1-dioxothian-4-yl,1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl,1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, C₁₋₃alkylsulfonyl, C₁₋₃alkylsulfonylamino, 1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl,piperidin-4-yl, piperidin-4-ylmethyl, and —OR₄; wherein R₄ is i)C₁₋₈alkyl optionally independently substituted with one or twoC₁₋₃alkoxy or hydroxy substituents; ii) C₃₋₇cycloalkyl; iii)4-hydroxy-1,1-dioxo-thian-4-ylmethyl; iv) 1,1-dioxothian-4-yl; v)1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl; vi)tetrahydro-2H-pyran-4-yl; vii) C₁₋₃alkylsulfonylpropyl; viii)2-(1-hydroxycyclopropyl)ethyl; ix) 3-methyloxetan-3-yl-methyl; x)(3-methyl-1, 1-dioxidothietan-3-yl)methyl; xi)(1-C₃₋₆cycloalkyl-1-ol)methyl; xii)4-hydroxy-tetrahydropyran-4-ylmethyl; xiii)2-(C₃₋₇cycloalkyl)-2-hydroxyethyl; xiv) tetrahydro-2H-pyran-4-ylmethyl;or xv) tetrahydrofuran-3-yl; R₅ is methyl, methoxy, bromo, chloro,C₁₋₆alkoxy-C₁₋₆alkoxyl, C₁₋₆ alkylsulfonyl, or trifluoromethyl; or anenantiomer, diastereomer, or pharmaceutically acceptable salt formthereof.
 2. The pharmaceutical composition of claim 1 comprising acompound of Formula (I) wherein ring W is phenyl.
 3. The pharmaceuticalcomposition of claim 1 comprising a compound of Formula (I) wherein ringW is pyridyl.
 4. The pharmaceutical composition of claim 1 comprising acompound of Formula (I) wherein A is —CH₂O—.
 5. The pharmaceuticalcomposition of claim 1 comprising a compound of Formula (I) wherein A is—OCH₂—.
 6. The pharmaceutical composition of claim 1 comprising acompound of Formula (I) wherein Z is CH, R₆ is hydrogen and R₁ is(S)-methylacetylenyl; or R₁ and R₆ are taken together to form aspirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl.
 7. Thepharmaceutical composition of claim 1 comprising a compound of Formula(I) wherein Z is N, R₆ is hydrogen and R₁ is (R)-methylacetylenyl; or R₁and R₆ are taken together to form a spirofused 3-hydroxycyclobutyl or aspirofused 3-oxocyclobutyl.
 8. The pharmaceutical composition of claim 1comprising a compound of Formula (I) wherein R₂ is hydrogen.
 9. Thepharmaceutical composition of claim 1 comprising a compound of Formula(I) wherein R₃ is hydrogen, chloro, or a substituent selected from thegroup consisting of C₁₋₃alkyl, hydroxy, 1,1-dioxothian-4-yl,1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl,1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, C₁₋₃alkylsulfonyl, C₁₋₃alkylsulfonylamino, 1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl,piperidin-4-yl, piperidin-4-ylmethyl, and —OR₄; wherein R₄ is i)C₁₋₈alkyl optionally independently substituted with one or twoC₁₋₃alkoxy or hydroxy substituents; ii) C₃₋₇cycloalkyl; iii)4-hydroxy-1,1-dioxo-thian-4-ylmethyl; iv) 1,1-dioxothian-4-yl; v)1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl; vi)tetrahydro-2H-pyran-4-yl; vii) C₁₋₃alkylsulfonylpropyl; viii)2-(1-hydroxycyclopropyl)ethyl; ix) 3-methyloxetan-3-yl-methyl; x)(3-methyl-1,1-dioxidothietan-3-yl)methyl; xi)tetrahydro-2H-pyran-4-ylmethyl; or xii) tetrahydrofuran-3-yl.
 10. Thepharmaceutical composition of claim 1 comprising a compound of Formula(I) wherein R₃ is hydrogen or a substituent that is —OR₄; wherein R₄ isi) C₁₋₄alkyl optionally independently substituted with one or twohydroxy or C₁₋₃alkoxy substituents; ii)(4-hydroxy-1,1-dioxo-thian-4-yl)methyl; iii)1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl; iv)tetrahydro-2H-pyran-4-yl; v) C₁₋₃alkylsulfonylpropyl; vi)tetrahydro-2H-pyran-4-ylmethyl; or vi) vii) tetrahydrofuran-3-yl. 11.The pharmaceutical composition of claim 1 comprising a compound ofFormula (I) wherein R₃ is selected from the group consisting ofhydrogen; methyl; hydroxy; chloro;(4-hydroxy-1,1-dioxo-thian-4-yl)methoxy; 4-(3-methylsulfonylpropoxy;1,1-dioxo-1,4-thiazinane-4-carbonyl;1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl; 1,1-dioxothian-4-yl;(1,1-dioxothian-4-yl)oxy; (1-hydroxycyclopropyl)ethoxy;3-hydroxy-3-methylbutoxy; 2,3-dihydroxypropoxy;(3-methyloxetan-3-yl)methoxy; (tetrahydro-2H-pyran-4-yl)oxy;2-methoxyethoxy; (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy;(3-methyl-1,1-dioxidothietan-3-yl)methoxy; (3-(methyl sulfonyl)propoxy;1,1-dioxidotetrahydro-2H-thiopyran-4-yl; 2-ethoxyethoxy;1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy;(tetrahydro-2H-pyran-4-yl)oxy;1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl; methylsulfonyl;methylsulfonamido; piperidin-4-yl; piperidin-4-ylmethyl; andtetrahydro-2H-pyran-4-yl)oxy.
 12. The pharmaceutical composition ofclaim 1 comprising a compound of Formula (I) wherein R₅ is methyl,methoxy, chloro, 2-methoxyethoxy, methanesulfonyl, or trifluoromethyl.13. A pharmaceutical composition comprising (a) a GPR40 agonist and (b)an SGLT2 inhibitor; wherein the GPR40 agonist is a compound of Formula(I)

wherein ring W is phenyl or pyridyl; A is —CH₂O— or —OCH₂—; Z is CH orN; R % is hydrogen; R₁ is selected from hydrogen or methylacetylenyl; orR₁ and R % are taken together to form a spirofused 3-hydroxycyclobutylor a spirofused 3-oxocyclobutyl; R₂ is hydrogen; R₃ is hydrogen, chloro,or a substituent selected from the group consisting of C₁₋₃alkyl,hydroxy, 1,1-dioxothian-4-yl, 1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl,1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, C₁₋₃alkylsulfonyl, C₁₋₃alkylsulfonylamino, 1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl,piperidin-4-yl, piperidin-4-ylmethyl, and —OR₄; wherein R₄ is i)C₁₋₈alkyl optionally independently substituted with one or twoC₁₋₃alkoxy or hydroxy substituents; ii) C₃₋₇cycloalkyl; iii)4-hydroxy-1,1-dioxo-thian-4-ylmethyl; iv) 1,1-dioxothian-4-yl; v)1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl; vi)tetrahydro-2H-pyran-4-yl; vii) C₁₋₃alkylsulfonylpropyl; viii)2-(1-hydroxycyclopropyl)ethyl; ix) 3-methyloxetan-3-yl-methyl; x)(3-methyl-1,1-dioxidothietan-3-yl)methyl; xi)tetrahydro-2H-pyran-4-ylmethyl; or xii) tetrahydrofuran-3-yl; R₅ ismethyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, ortrifluoromethyl; or an enantiomer, diastereomer, or pharmaceuticallyacceptable salt form thereof.
 14. The pharmaceutical composition ofclaim 13 comprising a compound of Formula (I) wherein when Z is CH, R₆is hydrogen and R₁ is (S)-methylacetylenyl; or R₁ and R₆ are takentogether to form a spirofused 3-hydroxycyclobutyl or a spirofused3-oxocyclobutyl; or, when Z is N, R₆ is hydrogen and R₁ is(R)-methylacetylenyl; or R₁ and R₆ are taken together to form aspirofused 3-hydroxycyclobutyl or a spirofused cyclobut-3-one-yl.
 15. Apharmaceutical composition comprising (a) a GPR40 agonist and (b) anSGLT2 inhibitor; wherein the GPR40 agonist is a compound of Formula (I)

wherein ring W is pyridyl; A is —CH₂O— or —OCH₂—; Z is CH, R₆ ishydrogen and R₁ is (S)-methylacetylenyl; or R₁ and R₆ are taken togetherto form a spirofused 3-hydroxycyclobutyl or a spirofused3-oxocyclobutyl; or Z is N, R₆ is hydrogen and R₁ is(R)-methylacetylenyl; or R₁ and R₆ are taken together to form aspirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl; R₂ ishydrogen; R₃ is hydrogen or a substituent that is —OR₄; wherein R₄ is i)C₁₋₄alkyl optionally independently substituted with one or two hydroxyor C₁₋₃alkoxy substituents; ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl; iv)tetrahydro-2H-pyran-4-yl; v) C₁₋₃alkylsulfonylpropyl; vi)tetrahydro-2H-pyran-4-ylmethyl; or vii) tetrahydrofuran-3-yl; R₅ ismethyl, methoxy, chloro, 2-methoxyethoxy, methanesulfonyl, ortrifluoromethyl; or an enantiomer, diastereomer, or pharmaceuticallyacceptable salt form thereof.
 16. A pharmaceutical compositioncomprising (a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein theGPR40 agonist is a compound of Formula (I)

wherein ring W is phenyl; A is —CH₂O— or —OCH₂—; when Z is CH, R₆ ishydrogen and R₁ is (S)-methylacetylenyl; or R₁ and R₆ are taken togetherto form a spirofused 3-hydroxycyclobutyl or a spirofused3-oxocyclobutyl; or when Z is N, R₆ is hydrogen and R₁ is(R)-methylacetylenyl; or R₁ and R₆ are taken together to form aspirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl; R₂ ishydrogen; R₃ is hydrogen or a substituent that is piperidin-4-yl,piperidin-4-ylmethyl, or —OR₄; wherein R₄ is i) C₁₋₄alkyl optionallyindependently substituted with one or two hydroxy or C₁₋₃alkoxysubstituents; ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl; iii)1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl; iv)tetrahydro-2H-pyran-4-yl; v) C₁₋₃alkylsulfonylpropyl; vi)tetrahydro-2H-pyran-4-ylmethyl; or vii) tetrahydrofuran-3-yl; R₅ ismethyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, ortrifluoromethyl; or an enantiomer, diastereomer, or pharmaceuticallyacceptable salt form thereof.
 17. A pharmaceutical compositioncomprising (a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein theGPR40 agonist is a compound of Formula (I)

wherein ring W is phenyl or pyridyl; A is —CH₂O—; when Z is CH, R₆ ishydrogen and R₁ is (S)-methylacetylenyl; or R₁ and R₆ are taken togetherto form a spirofused 3-hydroxycyclobutyl or a spirofused3-oxocyclobutyl; or when Z is N, R₆ is hydrogen and R₁ is(R)-methylacetylenyl; or R₁ and R₆ are taken together to form aspirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl; R₂ ishydrogen; R₃ is hydrogen or a substituent that is —OR₄; wherein R₄ is i)C₁₋₄alkyl optionally independently substituted with one or two hydroxylor C₁₋₃alkoxy substituents; ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl; iv)tetrahydro-2H-pyran-4-yl; v) C₁₋₃alkylsulfonylpropyl; vi)tetrahydro-2H-pyran-4-ylmethyl; or vii) tetrahydrofuran-3-yl; R₅ ismethyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, ortrifluoromethyl; or an enantiomer, diastereomer, or pharmaceuticallyacceptable salt form thereof.
 18. A pharmaceutical compositioncomprising (a) a GPR40 agonist and (b) an SGLT2 inhibitor; wherein theGPR40 agonist is a compound of Formula (I)

wherein ring W is phenyl or pyridyl; A is —CH₂O— or —OCH₂—; Z is CH orN; R₆ is hydrogen; R₁ is selected from hydrogen or methylacetylenyl; orR₁ and R₆ are taken together to form a spirofused 3-hydroxycyclobutyl ora spirofused 3-oxocyclobutyl; R₂ is selected from hydrogen or methyl; R₃is selected from the group consisting of hydrogen; methyl; methoxy;hydroxy; chloro; (4-hydroxy-1,1-dioxo-thian-4-yl)methoxy;4-(3-methylsulfonylpropoxy; 1,1-dioxo-1,4-thiazinane-4-carbonyl;1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl; 1,1-dioxothian-4-yl;(1,1-dioxothian-4-yl)oxy; (1-hydroxycyclopropyl)ethoxy;3-hydroxy-3-methylbutoxy; 2,3-dihydroxypropoxy;(3-methyloxetan-3-yl)methoxy; (tetrahydro-2H-pyran-4-yl)oxy;2-methoxyethoxy; (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy;(3-methyl-1,1-dioxidothietan-3-yl)methoxy; (3-(methyl sulfonyl)propoxy;1,1-dioxidotetrahydro-2H-thiopyran-4-yl; 2-ethoxyethoxy;1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy;(tetrahydro-2H-pyran-4-yl)oxy;1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl; methylsulfonyl;methylsulfonamido; 3-hydroxy-3-methylbutoxy;tetrahydro-2H-pyran-4-yl)methoxy; tetrahydrofuran-3-yloxy;piperidin-4-yl; piperidin-4-ylmethyl; and tetrahydro-2H-pyran-4-yl)oxy;R₅ is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, ortrifluoromethyl; or an enantiomer, diastereomer, or pharmaceuticallyacceptable salt form thereof.
 19. The pharmaceutical composition ofclaim 18 comprising a compound of Formula (I) wherein when Z is CH, R₁is (S)-methylacetylenyl; or R₁ and R₆ are taken together to form aspirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl; or, whenZ is N, R₁ is (R)-methylacetylenyl; or R₁ and R₆ are taken together toform a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl.20. A pharmaceutical composition comprising (a) a GPR40 agonist ofFormula (I) and (b) an SGLT2 inhibitor;

wherein the GPR40 agonist is selected from the group consisting of Cpd1,3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]propanoicacid; Cpd 2,(3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 3,(3S)-3-[4-[[3-[4-[(4-Hydroxy-1,1-dioxo-thian-4-yl)methoxy]-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 4,(3S)-3-[4-[[3-[2-Methyl-4-(3-methylsulfonylpropoxy)phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 5,(3S)-3-[4-[[3-[4-(1,1-Dioxo-1,4-thiazinane-4-carbonyl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 6,(3S)-3-[4-[[3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 7,(3S)-3-[4-[[3-(4-Hydroxy-2-methyl-phenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 8,(3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 9,(3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)oxy-2-methyl-phenyl]-2-methyl-benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid; Cpd 10,(3S)-3-[4-[[3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; Cpd 11,(3S)-3-(4-((3-(4-(2-(1-Hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 12,(3S)-3-(4-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 13,(3S)-3-(4-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 14,(3S)-3-(4-((3-(2-Methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 15,(3S)-3-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 16,(3S)-3-(4-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 17,(3S)-3-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 18,(3S)-3-(4-((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 19,(3S)-3-(4-((3-(2-Chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid; Cpd 20,(3S)-3-(4-((3-(2-Bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid; Cpd 21,(3S)-3-(4-((3-(2-(Trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 22,(3S)-3-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 23,(3S)-3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid; Cpd 24,(3S)-3-(4-(((3-(2-Methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid; Cpd 25,(3S)-3-(4-(((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid; Cpd 26,(3S)-3-(4-(((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid; Cpd 27,(3S)-3-(4-(((3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid; Cpd 28,2-(1-(4-((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid; Cpd 29,2-(1-(4-((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid; Cpd 30,2-(3-Oxo-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid; Cpd 31,2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid; Cpd 32,2-(1-(4-((3-(4-(2-Ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid; Cpd 33,2-(1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid; Cpd 34,2-(1-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid; Cpd 35,2-((1r,3r)-3-Hydroxy-1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid; Cpd 36,2-((1r,3r)-1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-hydroxycyclobutyl)aceticacid; Cpd 37,2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid; Cpd 38,2-(1-(4-((3-(2-Methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid; Cpd 39,2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)aceticacid; Cpd 40,2-(1-(4-((3-(4-(1,1-Dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)aceticacid; Cpd 41,(3S)-3-(4-((3-(2-Methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 42,(3S)-3-(4-((3-(2-Methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 43,(3S)-3-(4-((3-(2-Methyl-5-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 44,(3S)-3-(4-((3-(2-Methyl-6-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 45,3-(6-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd 46,3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd47,3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 48, (3S)-3-(4-((3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 49,(3S)-3-(4-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 50,(3S)-3-(4-((3-(6-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 51,(3S)-3-(4-((3-(6-(2-Methoxyethoxy)-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 52,(3S)-3-(4-((3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 53,3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)propanoicacid; Cpd 54,(3S)-3-[4-[([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid; Cpd 55,(3S)-3-[4-[([3-[4-(2,3-Dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid; Cpd 56,(3S)-3-(4-[[(3-[2-Methyl-4-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoicacid; Cpd 57,(3S)-3-[4-[([3-[2-Methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid; Cpd 58,(3S)-3-[4-[([3-[4-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid; Cpd 59,(3S)-3-{4-[((3-{4-[(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)oxy)methyl]phenyl}hex-4-ynoicacid; Cpd 60,(3S)-3-(4-(((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoicacid; Cpd 61,3-[6-([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)pyridin-3-yl]hex-4-ynoicacid; Cpd 62,3-(6-((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 63, 3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd 64,3-(6-((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 65,(3S)-3-[4-([3-[5-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid; Cpd 66,(3S)-3-[4-([3-[2-(2-Methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid; Cpd 67,(3S)-3-[4-([3-[3-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid; Cpd 68,(3S)-3-[4-([3-[2-(2-Methoxyethoxy)phenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoicacid; Cpd 69,(3S)-3-(4-[[3-(2-Methanesulfonylphenyl)-1-benzothiophen-6-yl]methoxy]phenyl)hex-4-ynoicacid; Cpd 70,(3S)-3-(6-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd 71,(3R)-3-(6-((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 72,(3S)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 73,(3R)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 74,(3S)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 75,(3R)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 76, (3S)-3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd 77,(3R)-3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd 78,(3S)-3-(4-((3-(2-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 79,(3S)-3-(4-((3-(2-Methoxyphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 80,(3S)-3-(4-((3-(6-Methoxy-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 81,(3S)-3-(4-((3-(4-Methoxypyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 82,(3S)-3-(4-((3-(6-Methoxy-4-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 83,(3S)-3-(4-((3-(3-Methoxypyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 84,(3S)-3-(4-((3-(5-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 85,(3R)-3-[6-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]pyridin-3-yl]hex-4-ynoicacid; Cpd 86,(3S)-3-[4-[([3-[2-Methyl-4-(tetrahydrofuran-3-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoicacid; Cpd 87, (3R)-3-(6-((3-(5-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd 88,(3R)-3-(6-((3-(3-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid; Cpd 89,(3R)-3-(6-((3-(5-(2-Methoxyethoxy)-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 90,(3R)-3-(6-((3-(2-Chloro-5-methylpyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoicacid; Cpd 91,(3S)-3-(4-((3-(3-Methoxypyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 92,(3R)-3-(6-((3-(5-(2-Methoxyethoxy)-2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)methoxy)pyridine-3-yl)hex-4-ynoicacid; Cpd 93,(3S)-3-(4-((3-(6-Chloro-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 94,(3S)-3-(4-((3-(6-Methoxy-3-methylpyridin-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 95,(3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 96,(3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; Cpd 97,3-(4-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid; and Cpd 98,(3R)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid; or a pharmaceutically acceptable salt form thereof.
 21. Thepharmaceutical composition of claim 20 wherein the SGLT2 inhibitor isselected from the group consisting of canagliflozin, dapagliflozin,empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin,bexagliflozin, ertugliflozin, ISIS 388626, remogliflozin, sergliflozinetabonate, and sotagliflozin.
 22. The pharmaceutical composition ofclaim 21 wherein the SGLT2 inhibitor is canagliflozin.
 23. Thepharmaceutical composition of claim 1 and at least one of apharmaceutically acceptable carrier, a pharmaceutically acceptableexcipient, and a pharmaceutically acceptable diluent.
 24. Thepharmaceutical composition of claim 23, wherein the composition is asolid oral dosage form.
 25. The pharmaceutical composition of claim 23,wherein the composition is a syrup, an elixir or a suspension.
 26. Apharmaceutical composition comprising (a) a GPR40 agonist of Formula (I)that is3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoicacid, Cpd 97

and (b) an SGLT2 inhibitor.
 27. The pharmaceutical composition of claim26 wherein the SGLT2 inhibitor is selected from the group consisting ofcanagliflozin, dapagliflozin, empagliflozin, ipragliflozin,luseogliflozin, tofogliflozin, bexagliflozin, ertugliflozin, ISIS388626, remogliflozin, sergliflozin etabonate, and sotagliflozin. 28.The pharmaceutical composition of claim 27 wherein the SGLT2 inhibitoris canagliflozin.
 29. The pharmaceutical composition of claim 28 and atleast one of a pharmaceutically acceptable carrier, a pharmaceuticallyacceptable excipient, and a pharmaceutically acceptable diluent.
 30. Apharmaceutical composition comprising (a) a GPR40 agonist of Formula (I)that is(3S)-3-[4-[[3-(2-methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoicacid, Cpd 2

and (b) an SGLT2 inhibitor.
 31. The pharmaceutical composition of claim30 wherein the SGLT2 inhibitor is selected from the group consisting ofcanagliflozin, dapagliflozin, empagliflozin, ipragliflozin,luseogliflozin, tofogliflozin, bexagliflozin, ertugliflozin, ISIS388626, remogliflozin, sergliflozin etabonate, and sotagliflozin. 32.The pharmaceutical composition of claim 31 wherein the SGLT2 inhibitoris canagliflozin.
 33. The pharmaceutical composition of claim 32 and atleast one of a pharmaceutically acceptable carrier, a pharmaceuticallyacceptable excipient, and a pharmaceutically acceptable diluent.
 34. Amethod of treating a disorder modulated by the GPR40 receptor and/orSGLT2 transporter, comprising administering to a subject in need thereofa therapeutically effective amount of the pharmaceutical composition ofclaim
 1. 35. A method of treating a disorder, wherein said disorder isaffected by the agonism of the GPR40 receptor and/or inhibition of SGLT2transporter, comprising administering to a subject in need thereof atherapeutically effective amount of the pharmaceutical composition ofclaim
 1. 36. The method of claim 35 wherein said disorder is selectedfrom the group consisting of Type II diabetes mellitus, hyperglycemia,hyperinsulinemia, obesity, obesity-related disorders, impaired glucosetolerance, insulin resistance, hypertriglyceridemia, metabolic syndrome,diabetic complications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema, that are related to GPR40 andSGLT2 transporter modulation.
 37. The method of claim 36 wherein thedisorder is Type II diabetes mellitus.
 38. A method of treating adisorder selected from the group consisting of Type II diabetesmellitus, hyperglycemia, hyperinsulinemia, obesity, obesity-relateddisorders, impaired glucose tolerance, insulin resistance,hypertriglyceridemia, metabolic syndrome, diabetic complications,atherosclerosis, diabetic nephropathy, other cardiovascular risk factorssuch as hypertension and cardiovascular risk factors related tounmanaged cholesterol and/or lipid levels, osteoporosis, inflammation,and eczema, that are related to GPR40 and SGLT2 transporter modulation,comprising administering to a subject in need thereof a therapeuticallyeffective amount of the pharmaceutical composition of claim
 1. 39. Amethod of treating a condition selected from the group consisting ofType II diabetes mellitus, hyperglycemia, hyperinsulinemia, obesity,obesity-related disorders, impaired glucose tolerance, insulinresistance, hypertriglyceridemia, metabolic syndrome, diabeticcomplications, atherosclerosis, diabetic nephropathy, othercardiovascular risk factors such as hypertension and cardiovascular riskfactors related to unmanaged cholesterol and/or lipid levels,osteoporosis, inflammation, and eczema, that are related to GPR40 andSGLT2 transporter modulation, comprising administering to a subject inneed thereof, a therapeutically effective amount of the pharmaceuticalcomposition of claim 1.